Humans are exposed to a wide range of dietary calcium intakes with potential for seasonal fluctuation as well as evidence of diurnal variation in calcium status because homeostasis is maintained through sleep–wake cycles and pulsed intakes, related to meals (Redmond et al., 2014). Serum calcium levels are controlled by several factors responsible for optimizing absorption and maintaining eucalcemia. Classically we think in terms of
l calcium absorption from the diet, particularly with reference to vitamin D—25-hydxoxy-vitamin D (25(OH)D) supply and 1,25-dihydroxy-vitamin D (1,25(OH)2D) action;
l excretion or reabsorption of calcium by the kidney, influenced by parathyroid hormone (PTH); and
l buffering of calcium in the skeleton (Redmond et al., 2014).
When dietary calcium intake is high, it crosses the intestinal epithelium by a paracellular pathway that involves the pas- sive movement of calcium through tight junctions between epithelial cells down a concentration gradient; this process is only affected indirectly by 1,25(OH)2D. Conversely, with moderate- or low-intake levels, active, transcellular transport is promoted by 1,25(OH)2D, which increases the synthesis of calbindin D9k to control movement of calcium across entero- cytes (Blaine et al., 2014).
In the kidney, 100–200 mg of calcium is excreted every day, which is less than 2% of the total filtered load of calcium, the vast majority of which is reabsorbed by the renal tubules (60–70% occurring in the proximal convoluted tubule, mostly by passive transport). In the loop of Henle, 20% of calcium reabsorption occurs by a combination of passive and active transport, and then approximately 10% occurs in the distal convoluted tubule, entirely by active transport because it is against an electrochemical gradient. Although the distal part of the nephron reabsorbs less than 10% of the filtered calcium load, it is the focus for regulating calcium excretion, under the predominant influence of PTH (Blaine et al., 2014). In renal disease, the control of calcium homeostasis (together with phosphate and acid-base balance) becomes important because the kidney is the site of calcium excretion and the synthesis of 1,25(OH)2D.
More than 99% of calcium is retained within the skeleton, although only 1% of this is freely exchangeable with extra- cellular fluid. Hence the physiological buffering capacity of bone is dependent on a relatively small proportion of skeletal mass. There is evidence of diurnal variation in calcium homeostasis, with low serum calcium being noted at night and higher PTH in the afternoon and at night. There is also evidence of diurnal variation in bone turnover, with apparent rises in markers of bone resorption after fasting, possibly under the influence of PTH (Redmond et al., 2014). The implications are that gut absorption and renal retention of calcium are important in the maintenance of blood calcium levels, with some involvement of the skeleton, in response to diurnal change. The evidence suggests that bone can be accessed to maintain extracellular calcium levels, and this is certainly important in disease states. For example, hyperparathyroidism, whether due to a primary parathyroid adenoma or an increase in PTH secondary to renal disease or vitamin D deficiency, may result in significant bone resorption (Fig. 5.1).
Vitamin D status is important for calcium homeostasis, but a detailed discussion is beyond the immediate scope of this chapter. Although 1,25(OH)2D is required to optimize calcium absorption, its precursor, 25(OH)D, is generally agreed to be the best biomarker for assessing vitamin D status. However, the threshold of 25(OH)D defining vitamin D deficiency is less generally agreed upon, ranging from 25 to 75 nmol/L (Francis et al., 2013). Reduction in plasma 25(OH)D is associated with the mineralization defect of bone seen in children as rickets and in adults as osteomalacia; less severe deficiency may still lead to secondary hyperparathyroidism, increased bone resorption, bone loss, impaired muscle function, and an increased risk of falls and fragility fractures (Bischoff-Ferrari, 2012; Bischoff-Ferrari et al., 2009a; Rejnmark et al., 2012). Particularly for children, deficiency effects of vitamin D and calcium can be closely linked, with nutritional rickets appearing to be a response to varying levels of vitamin D deficiency and low dietary calcium intake, depending on the population affected (Pettifor, 2013).
Dietary Calcium Requirements
Dietary calcium intake recommendations should be defined as the level of intake below or above which there is a risk to health. The Institute of Medicine (IOM) report on calcium and vitamin D is a comprehensive assessment of the evidence and discusses at length the methods used in its risk assessment that uses a framework to assess a range of factors: from
TABLE 5.1 Some of the Essential Functions of Calcium in the Body
Function Comment
Neuromuscular activity Nerves and muscle fibers use calcium ions as their main regulatory and signaling molecule.
Membrane function Calcium-dependent channels are found throughout the body, from phospholipases to mitochondria.
Hormone secretion Calcium ions move across membranes in a range of secretory organs, including the parathyroid gland, thyroid, and β cell.
Enzyme activity Several enzymes are sensitive to ambient calcium levels in the intracellular or extracellular space.
Blood coagulation Calcium levels are important at several stages in the intrinsic pathway of coagulation.
Skeletal mineralization and strength
The mineralization of bone matrix and formation of calcium hydroxyapatite is an important contributor to skeletal strength.
Mineral reservoir Calcium within bone mineral acts as a useful buffer to be released when serum calcium levels are low, and the resorption of calcium at the kidney is insufficient to meet the needs.
Calcium: Basic Nutritional Aspects Chapter | 5 47
6HUXP
&D .LGQH\
6PDOO,QWHVWLQH
%RQH 1HWH[FUHWLRQ
PJ &D 1HWDEVRUSWLRQ
PJ &D
1HJOLJLEOH 6KLIWVLQ&D
2+'
37+
3DUDWK\URLG*ODQG
.LGQH\
6PDOO,QWHVWLQH
%RQH VHUXP
&D
VHUXP
&D
2+'
2+'
37+
3DUDWK\URLG*ODQG
.LGQH\
6PDOO,QWHVWLQH
%RQH ,QFUHDVHG&DWXUQRYHU
:LWKQHWUHVRUSWLRQ ,QFUHDVHG&D
$EVRUSWLRQ 'HFUHDVHG
&D&OHDUDQFH
$
%
&
FIGURE 5.1 Calcium homeostasis and control of serum calcium levels, at the kidney, intestine, and in the skeleton under the influence of parathyroid hormone (PTH), 25-hydroxy-vitamin D (25(OH)D), and 1,25-dihydroxy-vitamin D (1,25(OH)2D). (A) Net changes in calcium in a balanced state, with equal absorption and renal reabsorption. (B) Lower serum calcium levels result in an increase in PTH, which also promotes conversion of 25(OH)D to 1,25(OH)2D. (C) An increase in PTH stimulates renal reabsorption of calcium and an increase in 1,25(OH)2D, which promotes active absorption of cal- cium via calmodulin and more chronically active resorption of skeleton to release calcium (as does an increase in PTH—not presented in the figure). See text for more details.
Hazard Identification to Hazard Characterization, Intake Assessment, and Risk Identification. The choice of biomarkers presents a potential issue, with a dominance in this area of vitamin D status markers. However, the IOM report suggests that a range of health outcome indicators exist that might be considered in evaluating calcium (and vitamin D) nutrition, including cancer risk, cardiovascular disease (CVD), diabetes, pregnancy outcomes, and skeletal health (Ross and Institute of Medicine (U.S.) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, 2011).
Dietary calcium requirements might be physiologically defined in terms of an intake threshold at which neutral cal- cium balance is achieved (i.e., where there is no difference between the total calcium intake and the sum of urinary and endogenous fecal calcium loss). Studies to evaluate calcium balance are difficult to perform, but results from such studies in adults aged 50 years or younger did form the basis for the IOM recommendations on dietary calcium (Ross and Institute of Medicine (U.S.) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, 2011). Throughout the course of life, we are in varying stages of calcium balance, through skeletal growth in infancy and childhood and on to menopausal bone loss for women and continued bone loss for both sexes in older adult life. Interactions between calcium balance and other factors, not the least being vitamin D, but also phosphate, protein, and endogenous sex hormones, will make individual requirements vary. However, estimates are remarkably robust, giving balance for adults at levels between 700 and 750 mg calcium per day.
In this chapter we shall not focus solely on physiological calcium balance but on aspects of relevance to calcium status and health, including skeletal health and other issues such as cardiovascular and renal stone disease. When considering the health implications of calcium intake, in addition to choice of biomarkers, there is a need to consider developmental stage of the life so that recommendations are likely to differ between the sexes and at different ages. However, further consideration of the identification of dietary calcium requirements will be left until later in the chapter.