2Overview of Calcium

INTRODUCTION

Calcium as a nutrient is most commonly associated with the formation and metabolism of bone. Over 99 percent of total body calcium is found as calcium hydroxyapatite (Ca₁₀[PO₄]₆[OH]₂) in bones and teeth, where it provides hard tissue with its strength. Calcium in the circulatory system, extracellular fluid, muscle, and other tissues is critical for mediating vascular contraction and vasodilatation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion. Bone tissue serves as a reservoir for and source of calcium for these critical metabolic needs through the process of bone remodeling.

Calcium metabolism is regulated in large part by the parathyroid hormone (PTH)–vitamin D endocrine system, which is characterized by a series of homeostatic feedback loops. The rapid release of mineral from the bone is essential to maintain adequate levels of ionized calcium in serum. During vitamin D deficiency states, bone metabolism is significantly affected as a result of reduced active calcium absorption. This leads to increased PTH secretion as the calcium sensing receptor in the parathyroid gland senses changes in circulating ionic calcium. Increased PTH levels induce enzyme activity (1α-hydroxylase) in the kidney, which converts vitamin D to its active hormonal form, calcitriol. In turn, calcitriol stimulates enhanced calcium absorption from the gut. Not surprisingly, the interplay between the dynamics of calcium and vitamin D often complicates the interpretation of data relative to calcium requirements, deficiency states, and excess intake.

SOURCES OF CALCIUM

Ingested calcium comes from food sources and dietary supplements. In this report dietary calcium refers to both food sources and supplements combined (although some researchers reserve the term dietary calcium to mean only food sources) and is most often referred to as total calcium intake for clarity. With more than one-half of the U.S. population (Bailey et al., 2010)—and between 24 and 60 percent of Canadians (2004 Canadian Community Health Survey, personal communication, D. Brulé, Health Canada, April 29, 2010)—reporting use of dietary supplements of some type, dietary supplements must be taken into account when considering the sources of calcium in the diet and, in turn, estimating total calcium intake. Current estimates from 2003 to 2006 indicate that the median total intake of calcium from all sources for persons > 1 year of age ranges from 918 to 1,296 mg/day, depending upon life stage (Bailey et al., 2010). Only small amounts of calcium are contributed by water, depending upon geographic location. Chapter 7 of this report contains an assessment of quantitative calcium intake in the U.S. and Canadian populations.

METABOLISM OF CALCIUM

Homeostatic Regulation of Calcium

Maintaining the level of circulating ionized calcium within a narrow physiological range is critical for the body to function normally, and control of serum calcium levels is maintained through an endocrine system—a system of glands that secrete hormones and is characterized by controlling factors and feedback mechanisms—that includes a major role for vitamin D metabolites, principally calcitriol, and PTH. Calcium balance within the body is closely linked to the hormonal actions of calcitriol. The vitamin D-related endocrine system that maintains serum calcium levels is discussed in Chapter 3 but is also summarized below and illustrated in Figure 2-1.

FIGURE 2-1

Endocrine feedback system that maintains serum calcium levels: Involvement of vitamin D and parathyroid hormone (PTH). NOTE: CT = calcitonin; PTG = parathyroid gland. SOURCE: Reprinted with permission from Hector DeLuca.

The vitamin D metabolic system forms the basis of the calcium homeostatic mechanism in mammals. Total calcium concentration in serum is tightly regulated to remain between 8.5 and 10.5 mg/dL (2.12 and 2.62 mmol/L). If this level deviates slightly, the calcium sensing receptor of the parathyroid gland signals the secretion of PTH, which functions as a calcium sensor. PTH then stimulates the kidney to produce calcitriol, the hormonal form of vitamin D, as well as to activate bone resorption, which will increase extracellular calcium levels. Calcitriol acts in an endocrine manner on the intestine, bone, and kidney to raise serum calcium levels; it also acts on the intestine and, to some extent, the kidneys to raise serum phosphorus levels. As the serum calcium level rises, the feedback mechanism causes the calcium sensing receptor to be turned off and PTH secretion to drop. If there is an overshoot in serum calcium levels, the “C” cells (parafollicular) cells of the thyroid gland secrete calcitonin, which can block bone calcium resorption, helping to keep serum calcium levels in the normal range. Calcitriol, through its receptor, also provides feedback relative to suppressing the production and release of PTH, commonly referred to as PTH suppression. Not shown in the figure is that calcitriol is also directly controlled by the serum phosphorus level; a high serum phosphorus level suppresses the formation of calcitriol, whereas a low level stimulates it.

FUNCTIONS AND PHYSIOLOGICAL ACTIONS OF CALCIUM

Calcium is an integral component of the skeleton, and the skeleton provides a reservoir of calcium for other essential calcium-dependent functions throughout the body. The skeleton serves at least three main functions. First, calcium, as part of the mineral hydroxyapatite, deposited into the organic matrix of the skeleton, is critical for its structure and is necessary for tissue rigidity, strength, and elasticity. This function allows for normal movement and exercise. Second, the skeleton functions as a source of minerals and alkali and therefore is critical for overall mineral homeostasis. The skeleton is the principal depot for calcium, containing 98 percent of total body calcium. It can be called on repeatedly, through the processes of bone formation and resorption (referred to as remodeling, as discussed below), to maintain circulating levels of calcium at a constant level. While the same qualitative processes apply to skeletal calcium metabolism across the life cycle, there are quantitative differences by age and hormonal status. These life cycle differences for skeletal growth and remodeling are discussed in a section below. Excessive calcium resorption can compromise the integrity and strength of the skeletal tissues. Third, the marrow cavity of bone serves as a major site for the development of hematopoietic cells and as a major compartment of the immune system. Several of the cell types involved in bone remodeling originate in the bone marrow compartment. Stromal or connective tissue cells are found in the bone marrow; at one time, these were thought to be inert, but they are now considered multi-potent stem cells that can become either fat or bone cells under the influence of specific differentiation factors (Muruganandan et al., 2009).

A principal physiological function of calcium apart from its role in maintaining the skeleton, is as an essential intracellular messenger in cells and tissues throughout the body. Although this pool of calcium is quantitatively small, the ionized calcium present in the circulatory system, extracellular fluid, muscle, and other tissues, is critical for mediating vascular contraction and vasodilatation, muscle function, nerve transmission, and hormonal secretion. Ionized calcium is the most common signal transduction element in biology, owing to its ability to reversibly bind to proteins and to complex with anions such as citrate and bicarbonate (Weaver and Heaney, 2006b).

Bone Formation and Remodeling

Bone is composed of a mineral compartment, predominantly calcium hydroxyapatite and an organic matrix, osteoid, composed principally of collagen and non-collagenous proteins and growth factors. The relative contributions of the mineralized and organic compartments depend on the age of the individual; in general, 50 to 70 percent of bone is mineral, 20 to 40 percent is organic matrix, and the rest is water and lipid. The organic matrix is critical for both the structural and functional components of the skeleton, providing elasticity and contributing to regenerative and remodeling properties. Much of the organic matrix is composed of type I collagen fibrils that are organized in such a manner that strength and elasticity are combined. Numerous non-collagenous proteins are also present in the organic matrix. Some of them, such as osteocalcin and matrix GLA protein, contain γ-carboxyglutamate, an amino acid with high affinity for calcium that is required for proper mineralization of the matrix (see below). The role of phosphate in bone development should not be overlooked. As described below, first phosphorus is laid down during the mineralization process, and then calcium binds to it. Calcitriol stimulates the uptake of both calcium and phosphorus from the intestine.

Development

The skeleton develops through a process of either intramembranous or endochondral bone formation, depending on location and function. Intramembranous bone formation is the predominant process in the skull, whereas endochondral bone formation occurs in long bone and the axial skeleton. Intramembranous bone is formed by direct differentiation of mesenchymal precursors into osteoblasts, cells of the fibroblast–stromal lineage that produce bone matrix proteins and synthesize a lattice for subsequent mineralization. In contrast, during endochondral bone formation chondrocytic differentiation occurs first, leading to a soft cartilaginous infrastructure. The cartilage then becomes calcified, and the provisional calcified cartilage is subsequently replaced by bone. This occurs by vascular invasion, which allows entry of hematopoietic precursors and osteoclasts, macrophage-like cells that originate from the monocyte–macrophage lineage, which remove apoptotic chondrocytes and cartilage (Provot and Schipani, 2007). New bone is formed by osteoblasts. Osteoblastogenesis follows chondrogenesis after release of growth factors from terminally differentiated chondrocytes. The first bone formed is woven and relatively unorganized. However, through osteoclastic modeling that bone is replaced by lamellar bone, which is highly organized and provides the strength necessary to support soft tissue (Yang and Yang, 2008).

Endochondral bone formation allows for linear development of the growth plate as well as periosteal expansion, which ultimately results in a longer and thicker bone. Mineralization is the final stage in terminal differentiation of the osteoblast and occurs through a complex process whereby ion deposition is followed by crystal formation between the collagen fibrils. This occurs because of undersaturation of calcium hydroxyapatite in the extracellular fluid and the binding of calcium to non-collagenous proteins in the matrix (Favus, 2008). Initially, phosphate drives the mineralization by being laid down in bone as hydroxyapatite; the negative charge of hydroxyapatite then causes calcium to avidly bind to it. In states of phosphorus deficiency, unmineralized osteoid persists despite adequate calcium intake. Bone mechanical properties are then influenced by the distribution, size, and density of the apatite crystals. Too much or too little mineral can lead to impaired bone strength; the former makes the bone too brittle, whereas the latter makes the bone too ductile and weak.

Remodeling

Calcium balance is preserved within the non-bone tissues of the body, because adult bone constantly undergoes remodeling through bone resorption, mainly by osteoclasts and bone formation mainly by osteoblasts.³ Terminology associated with remodeling is shown in Box 2-1. In adults, virtually all of the human skeleton is remodeled over a 10-year cycle, although trabecular bone turns over more readily. In contrast, bone formation incorporates calcium into the matrix, and this process requires significant time and energy. Overall calcium balance is maintained at the skeletal level by opposing actions of bone cells. Skeletal remodeling occurs in microscopic elements of bone referred to as remodeling units or basic multicellular units, which contain the osteoblasts (bone-resorbing cells) and osteoclasts (bone-forming cells). Old osteoblasts then become osteocytes entombed within the bone matrix after mineralization.

BOX 2-1

Bone Remodeling Terms and Definitions. Cortical bone: One of two types of bone; makes up the outer part of all skeletal structures (nearly 80 percent of the skeleton); is dense and compact with a slow turnover rate and is highly resistant to bending and (more...)

The axial and appendicular skeletons are composed of both cortical and trabecular bone. The hard outer shell of bone is cortical, which is remodeled less frequently, but is important for strength and periosteal expansion during puberty and with aging. The trabecular compartment is bathed by bone marrow and is remodeled much more frequently, which is in part due to a much greater surface area and the existence of marrow elements that are in close proximity to the endosteal surface of bone (which contribute progenitor cells for eventual remodeling).

Physical activity—or more specifically mechanical loading—is a critical component of skeletal homeostasis. It is thought that osteocytes in cortical bone sense changes in gravitational forces and elaborate growth factors that initiate remodeling. Unloading of the skeleton in cases such as bed rest or weightlessness (space travel) is associated with a profound uncoupling of remodeling, such that bone resorption is dramatically increased, whereas bone formation is suppressed. These changes cause rapid bone loss and are a major problem for long-term spaceflight. Loading of the skeleton by mechanical means (e.g., weight-bearing exercise such as running, walking, or jumping) can promote bone formation, particularly in early childhood and adolescence, although it has benefits later in life as well.

Concept of Normal, Healthy Bone Accretion

Bone is a dynamic tissue; it is metabolically active, responding to both genetically determined and environmental stimuli that ultimately determine its composition and structural integrity. Bone modeling describes events that occur primarily during growth resulting in increased bone size and modification of its shape in response to genetic determinants and mechanical loading. Bone remodeling occurs in response to stimulation by surface-dependent factors initiated by damage or mechanical loading. It includes bone resorption and deposition but does not alter the size or shape of bone (reviewed in Seeman, 2009).

Although the role of genetic and environmental factors in bone modeling and remodeling has long been debated in the literature, genetics remains the chief determinant of bone mass, which, in turn, is the determinant of bone strength (Krall and Dawson-Hughes, 1993; Jouanny et al., 1995; Jones and Nguyen, 2000; Sigurdsson et al., 2008; Perez-Lopez et al., 2010). Given uncertainties in understanding the cumulative impact of genetic and environmental influences on bone mass across life stages, the question of whether attainment of maximal, optimal, or “peak” bone mass can be achieved on a lasting basis through dietary manipulation and/or use of supplements has not been completely resolved.

A 2-year longitudinal multiethnic study (Abrams et al., 2000) of changes in calcium absorption, bone accretion, and markers of bone growth in pre-pubertal girls (7 to 8 years of age) maintained on a calcium intake of 1,200 mg/day found a significant increase in calcium use associated with pubertal development. The increase paralleled markers of bone formation; supporting the hypothesis that calcium intake during the early to late pubertal stage influences peak rates of calcium gain in bone during pubertal development. An earlier study followed pre-pubertal males and females (mean age 8.5 years) for 18 months after calcium supplementation and also found gains in bone mineral content (BMC) and bone area of the lumbar spine; however, the increases in bone accretion disappeared after supplements were withdrawn (Lee et al., 1996). In a longer-term randomized clinical trial, Matkovic et al. (2005) evaluated the effects of calcium supplementation on bone accretion in the transition from childhood into early adulthood. This study found significant increases in bone accretion for total bone density, distal and proximal radius, and metacarpal indexes after 4 years of supplementation; by 7 years, however, only the proximal radius and metacarpal indexes still showed significantly increased bone accretion over non-supplemented controls.

These findings corroborate a role for calcium intake and skeletal size; however, they also suggest that bone accretion diminishes during skeletal consolidation in late adolescence, and attainment of a peak bone mass was transient for some skeletal sites, even though the study subjects continued calcium supplementation through year 7. When considered together, these studies support an increase in skeletal size and mineralization that occurs with calcium supplementation, but fail to show consistently that BMC is retained over the long term, particularly after supplementation is withdrawn.

Effect of Menopause

Studies of bone histomorphometry (Recker et al., 2004) and markers of bone remodeling (Uebelhart et al., 1990) indicate that bone remodeling is accelerated in the perimenopausal and postmenopausal periods. The span of 5 to 10 years surrounding menopause is characterized by a decrease in estrogen production and an increase in resorption of calcium from bone (Stevenson et al., 1981; Riggs, 2002; Masse et al., 2005; Finkelstein et al., 2008), resulting in a marked decrease in bone density. For example, Ebeling et al. (1996) measured changes in markers of bone mineral density (BMD) in a cohort of 281 women who were 45–57 years of age, and found the BMD in lumbar spine and femoral neck was decreased by 20 percent in perimenopausal and postmenopausal women compared with premenopausal women. The bone loss is most rapid in the early years of menopause, and then approximately 6 to 7 years postmenopause the loss continues at a slower rate (Pouilles et al., 1995)

The bone loss associated with menopause results from uncoupling in the bone remodeling units, such that resorption of bone is greater than formation of new bone. Over time, such changes lead to skeletal fragility and decreased bone mass. Some cohort studies demonstrate that accelerated bone loss is an independent risk factor for fracture, such that the combination of low bone mass and high rates of bone turnover markedly increase the potential for a future fracture (Garnero et al., 1996). Bone remodeling in postmenopausal osteoporosis includes changes in osteoid thickness, surface area, and volume. Parfitt et al. (1995) determined that defective osteoblast recruitment in women with osteoporosis resulted in decreased osteoid thickness, a characteristic of osteoporosis.

Considerable variability exists among women regarding the effects of menopause on bone loss, and such effects vary according to body mass index and ethnicity (Finkelstein et al., 2008). The effect of estrogen/progesterone treatment on preventing bone loss and reducing fracture risk is well established. However, the use of such therapy has declined as a result of recent reports of adverse non-skeletal effects. Because rapid bone loss occurs after estrogen treatment is discontinued (Gallagher et al., 2002), the potential impact on subsequent fracture rates is of interest but remains unclear.

Skeletal Disorders

Rickets and Osteomalacia

Rickets is the term for the end-stage condition in infants and children that begins with suboptimal bone mineralization at the growth plate and progresses with associated physiological perturbations that include secondary hyperparathyroidism, hypocalcemia, and hypophosphatemia leading to irreversible changes in skeletal structure. The disease is a disorder of the growth apparatus of bone in which growth cartilage fails to mature and mineralize normally. Because the bone is undermineralized it is also soft and ductile, and this leads to bowing of the limbs, widening and compression of the ends of the long bones, etc. The similar condition of osteomalacia (defective mineralization of bone and softening of bone) also occurs, and is seen in adults as well as children. Although these conditions are commonly associated with inadequate vitamin D exposure, each can also result from calcium (or phosphorus) deficiency. Rickets and osteomalacia due to a lack of calcium in the diet cannot be corrected by increasing levels of calcitriol (i.e., the active form of vitamin D also referred to as 1,25-dihyroxyvitamin D).

Rickets In rickets, during prolonged deficiency of calcium (and phosphate), the body increases PTH to prevent hypocalcemia by causing osteoclastic absorption of the bone. This, in turn, causes the bone to become progressively weaker, resulting in rapid osteoblastic activity. The osteoblasts produce large amounts of organic bone matrix, osteoid, which does not become calcified (Guyton and Hall, 2001). Consequently, the newly formed, uncalcified osteoid gradually takes the place of other bone that is being reabsorbed. During the later stages of rickets, the serum calcium level falls precipitously, and tetany (neuromuscular spasm) develops. In infants and young children, a long-standing calcium intake deficiency, in association with suboptimal vitamin D exposure, can produce rickets. Indeed, in experimental animals and in humans with extremely low vitamin D levels, genetic absence of calcitriol (vitamin D–dependent rickets [VDDR] type I), or genetic absence of the vitamin D receptor (VDDR type II), the use of increased calcium supplementation or calcium infusions will prevent and treat rickets. These observations indicate that the primary cause of rickets is inadequate delivery of calcium to the bone surface, not a defect in osteoblast function. In other words, the primary role for vitamin D and calcitriol in regulating skeletal homeostasis is indirectly accomplished by stimulating the intestinal absorption of calcium and phosphorus.

The clinical symptoms of rickets include stunted growth and bowing of the extremities. A serum 25-hydroxyvitamin D (25OHD) level of less than 27 to 30 nmol/L is not diagnostic of the disease but is associated with an increased risk for developing rickets (Specker et al., 1992).

Osteomalacia In osteomalacia, as seen in adults, the newly deposited bone matrix fails to mineralize adequately. Poor calcium intake is associated with secondary increases in PTH in an attempt to compensate for low serum calcium levels. The secondary hyperparathyroidism of calcium deficiency states is associated with increased bone resorption and suppression of bone formation. As a result, older adults who have calcium-poor diets and very low vitamin D levels may develop not only osteoporosis, as described below (i.e., a reduction in bone mass), but also osteomalacia (a reduction in mineral within the bone matrix). Osteomalacia is actually the clinical syndrome of undermineralization of bone associated with muscle weakness, bone pain, and fractures. The characteristic histological feature of osteomalacia is unmineralized matrix, which is often represented experimentally as the ratio of osteoid volume to bone volume. Ultimately, reductions in mineralization lead to impaired bone strength and significant softening of the skeleton. The calcium levels in the blood of patients with osteomalacia are often normal despite the undermineralization of bone, underscoring the importance of maintaining the blood calcium level over maintaining the mineralization of the skeleton. However, serum phosphorus levels are frequently low, PTH concentrations are 5 to 10 times the normal levels, and there is an increased level of alkaline phosphatase together with increased markers of bone turnover. Bone scans often indicate dramatically increased skeletal uptake by resident osteoblasts. As recognized by Parfitt et al. (1995) and illustrated by the histological classification scheme used for osteomalacia, what clinicians generally recognize as osteomalacia is the end-stage results from a prolonged severe deficiency of calcium and/or vitamin D. During the earliest stages (preosteomalacia), there exists a calcium-deficient state, even though the osteoid thickness, mineralization lag time, and osteoid volume are still normal. Subsequently, more dramatic changes occur including a greater increase in osteoid thickness, and impaired mineralization.

Osteomalacia is estimated to be present in about 4 to 5 percent of general medical and geriatric patients (Anderson, 1961; Stacey and Daly, 1989; Campbell et al., 1994). However, the clinical syndrome of bone pain, muscle weakness, and impaired bone mineralization is much less frequently recognized. In the face of severe osteoporosis, the diagnosis of osteomalacia can only be made by bone biopsy, usually using the method of double tetracycline labeling, demonstrating impaired mineralization of the skeleton (Villareal et al., 1991; Chapuy et al., 1992; Komar et al., 1993). In fact, osteomalacia is noted histologically in the bones of 20 to 40 percent of first-time hip fracture patients (Jenkins et al., 1973; Aaron et al., 1974; Sokoloff, 1978). These results suggest that these individuals may be presenting with a mixture of osteoporosis and osteomalacia. This clinical scenario can be related to both nutrient insufficiency and the coincidental progression of age-related bone loss.

Osteoporosis and Fractures

Osteoporosis is a skeletal disorder associated with aging and characterized by compromised bone strength due to reduced bone mass and reduced bone quality. Reduced bone mass—as measured by low BMD—increases bone fragility and, in turn, predisposes a person to an increased risk of fracture, notably at the vertebrae, hip, and forearm (NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001). As shown in Figure 2-2, the relationship between BMD measures and the incidence of fractures is notable. Overall, osteoporosis-related morbidity and mortality, as well as health care costs, are a significant public health concern (NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001). Osteoporosis is most commonly associated with women, but the condition also occurs in men.

FIGURE 2-2

Bone mineral density (BMD), osteoporotic fracture rate, and number of women with fractures. SOURCE: Siris et al. (2004). Archives of Internal Medicine 164(10): 1108-12. Copyright © 2004 American Medical Association. All rights reserved.

Menopause can initiate osteoporosis through elevated bone remodeling, which occurs characteristically in postmenopausal women. Remodeling activity, although designed to repair weakened bone, actually makes it temporarily weaker when remodeling is excessive. It can lead to enhanced skeletal fragility (Heaney, 2003). Although it is unclear to what extent calcium intake can mitigate such bone loss, inadequate calcium intake can exacerbate the situation.

Men experience age-related bone loss as well, although not due to menopause. This, in turn, can result in osteoporosis. However, the incidence of fracture risk increases some 5 to 10 years later in men than it does in women (Tuck and Datta, 2007).

CALCIUM ACROSS THE LIFE CYCLE

The body's need for calcium relative to skeletal growth and remodeling varies by life stage. The major physiological activities include bone accretion during skeletal growth and maintenance of bone mass after growth is completed. Later in adult life, net calcium is lost from the body when bone formation no longer keeps up with bone resorption. For all life stages highlighted below, specific studies and conclusions are detailed in Chapter 4.

BONE MASS MEASURES ASSOCIATED WITH CALCIUM

Several key bone mass measures are commonly used in the context of calcium nutriture and related health outcomes. The accumulation and level of bone mass can be determined using the calcium balance method or, alternatively, the measurement of BMC or BMD based on DXA. The latter method relies on the assumption that about 32 percent of the measured bone mineral is calcium (Ellis et al., 1996; Ma et al., 1999). These methods are described below.

Calcium Balance

Calcium balance (positive, neutral, or negative) is the measure derived by taking the difference between the total intake and the sum of the urinary and endogenous fecal excretion. Balance studies embody a metabolic approach to examining the relationship between calcium intake and calcium retention and are based on the assumption that the body retains the amount of calcium that is needed. As such, measures of calcium balance (or of “calcium retention”) can reflect conditions of bone accretion, bone maintenance, or bone loss. Calcium balance analyses involve measuring as precisely as possible the intake and the output of calcium. Output is usually reflected by urine and fecal calcium; sweat calcium is not usually measured, but its inclusion adds to the precision of the estimates. Calcium balance studies are expensive and require considerable subject cooperation owing to the prolonged stays in metabolic wards. Measures of calcium balance have limitations and are generally cross–sectional in nature, and their precision is difficult to ascertain. However, if well conducted, they provide valuable information on calcium requirements relative to the typical intake of the population under study. Long-term balance studies for calcium are generally not carried out because of the difficult study protocol. Calcium balance can also be estimated by using stable isotopes to trace the amount of calcium absorbed, usually in infants from a single feeding (Abrams, 2006).

Calcium balance outcomes that are positive are indicative of calcium accretion and are sometimes referred to as net calcium retention; neutral balance suggests maintenance of bone, and negative balance indicates bone loss. The relevance of the calcium balance state varies depending upon developmental stage. Infancy through late adolescence are characterized by positive calcium balance. In female adolescents and adults, even within the normal menstrual cycle, there are measurable fluctuations in calcium balance owing to the effects of fluctuating sex steroid levels and other factors on the basal rates of bone formation and resorption. Later in life, menopause and age-related bone loss lead to a net loss as a result of calcium due to enhanced bone resorption.

In the 1997 IOM report that focused on calcium DRIs (IOM, 1997), metabolic studies of calcium balance were used to obtain data on the relationship between calcium intakes and retention, from which a non-linear regression model was developed; from this was derived an intake of calcium that would be adequate to attain a predetermined desirable calcium retention.⁴ The approach used in 1997 was a refinement of an earlier approach suggested to determine the point at which additional calcium does not significantly increase calcium retention, called the plateau intake (Spencer et al., 1984; Matkovic and Heaney, 1992).

The balance studies included in the 1997 IOM report (IOM, 1997) met criteria that included the following: subjects had a wide range of calcium intakes, as variability in retention increases at higher intakes; the balance studies were initiated at least 7 days after starting the diet in order for subjects to approach a steady state, as observed by Dawson-Hughes et al. (1988); and, where possible, the adult balance studies included were only for subjects who were consuming calcium at their usual intakes, unless otherwise indicated. By selecting studies conducted on such subjects, the 1997 committee concluded that it obviated the concern about whether the bone remodeling transient (i.e., the temporary alteration in the balance between bone formation and bone resorption) might introduce bias in the calcium retentions observed (IOM, 1997). Such selection was not possible in studies in children who were randomized to one of two calcium intakes. However, in children, the impact of the bone remodeling transient related to changing intake is overshadowed by their rapid and constantly changing rates of calcium accretion (i.e., their modeling and remodeling rates are not in steady state, even without an intake change).

For the 1997 DRI development (IOM, 1997), the non-linear regression model describing the relationship between calcium intake and retention was solved to obtain a predetermined desirable calcium retention that was specific for each age group. According to the report, the major limitation of the data available was that bone mineral accretion during growth had not yet been studied over a wide range of calcium intakes. Overall, the committee expressed concern about the uncertainties in the methods inherent in balance studies.

Specifics about calcium balance studies that relate to DRI development are provided in Chapter 4, but, as background the recent work of Hunt and Johnson (2007) offers some remedy for the uncertainties surrounding the precision of balance studies. Hunt and Johnson (2007) examined data from 155 subjects—men and women between the ages of 20 and 75 years— who took part in 19 feeding studies conducted at one site (Grand Forks Human Nutrition Research Unit) between 1976 and 1995 in a metabolic unit under carefully controlled conditions.

In their overall analysis, the relationship between intake and output was examined by fitting random coefficient models. Rather than model calcium retention compared with calcium intake by using the Jackman et al. (1997) model, as was done in the 1997 DRI report (IOM, 1997), Hunt and Johnson (2007) modeled output rather than retention to avoid confounding in the precision of estimates that would be caused by including intake as a component of the dependent variable. In the Hunt and Johnson (2007) analysis, the data summary did not show non-linearity and therefore did not justify the use of a more complex non-linear model. The authors noted that the coefficients of the 1997 approach appeared to be greatly influenced by data points above the 99th percentile of daily calcium intake and pointed out that the data in their model reflected typical calcium intake between the 5th and approximately 95th percentiles for all boys and men 9 or more years of age, and between the approximately 25th and greater than 99th percentiles for all girls and women 9 or more years of age.

Hunt and Johnson (2007) also pointed out that most (but not all) studies with adults that indicate a positive influence of high total calcium in reducing the rate of bone remodeling were confounded by the presence of vitamin D as an experimental co-variable. In their study, the metabolic diets were similar to the estimated median intake of vitamin D by free-living young women. In short, the analysis may provide a reasonable approach for extracting meaningful data from calcium balance studies that are often confounded by multiple dietary factors. At this point, factorial methods should be briefly noted as the determination of calcium requirements has also made use of a factorial approach as noted in the 1997 DRI report (IOM, 1997). The factorial approach allows the estimate of an intake level that achieves the measured levels of calcium accretion/retention. The method combines estimates of losses of calcium via its main routes in apparently healthy individuals and then assumes that these losses represent the degree to which calcium intake, as corrected by estimated absorption, is required to balance these losses. The weakness in this method is that it is unusual for all of the necessary measurements to be obtained within a single study. Therefore, most calculations using the factorial approach are compiled from data in different studies and thus in different subjects; this can introduce considerable variation and confound the outcomes. This approach, as carried out in the 1997 IOM report on DRIs for calcium and vitamin D (IOM, 1997), where the interest was in desirable retention, is illustrated in Table 2-1.

TABLE 2-1

1997 DRI Factorial Approach for Determining Calcium Requirements During Peak Calcium Accretion in White Adolescents.

OTHER FACTORS RELATED TO CALCIUM NUTRITURE

As described above, not all calcium consumed is absorbed once it enters the gut. In general, the efficiency of calcium absorption is in reverse proportion to the amount of calcium consumed at any one time. Other factors also affect the amount of calcium available to the body.

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Footnotes

1

U.S. Department of Agriculture/Economic Research Service Nutrient Availability Data (2009). Available online at http://www​.ers.usda.gov​/Data/FoodConsumption​/NutrientAvailIndex.htm. Accessed October 19, 2010.

2

Other forms of calcium dietary supplements include lactate, gluconate, glucoheptonate, and hydroxyapatite; their relevance for life stage groups may vary.

3

Not all calcium enters the skeleton through bone formation or leaves the skeleton through bone resorption, as discussed by Parfitt (2003). Moreover, during lactation and in response to other acute demands for calcium, osteocytes have been shown to resorb the matrix surrounding them and then to restore it after the stress is over (Teti and Zallone, 2009).

4

A footnote to the 1997 IOM report (IOM, 1997) explains the decision not to base considerations on maximal calcium retention: The 1997 committee intended to use a recently described statistical model (Jackman et al., 1997) to estimate an intake necessary to support maximal calcium retention and from which to derive an EAR, and did so in the pre-publication of the report. In the original paper by Jackman et al. (1997), an estimate was made of the lowest level of calcium intake that was statistically indistinguishable from 100 percent maximal retention in some individuals. However, the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (DRI Committee) reviewed the approach in the pre-publication of the report and adopted a different interpretation of the data for the purpose of establishing an AI. The 1997 committee was subsequently advised that there were both statistical and biological concerns with the application of the percent maximal retention model (presented in Appendix E of the 1997 IOM report [IOM, 1997]). The final print of the 1997 report retained the statistical model described by Jackman et al. (1997), but applied it to determine, from the same calcium balance data as was used in the pre-publication report, an estimate of the calcium intake that is sufficient to achieve a defined, desirable level of calcium retention specific to the age groups considered.

5

Available online at http://ods​.od.nih.gov​/factsheets/calcium/ (accessed July 23, 2010).