Calcium: Definition, Synthesis, Absorption, Transport, and Distribution

Calcium is a chemical element with the element symbol Ca and atomic number 20. It belongs to the group of alkaline earth metals and is the fifth most abundant element on Earth. Calcium represents an essential (vital) mineral for humans and occurs in the organism exclusively as a divalent cation (Ca2+).

Absorption

Food-bound calcium must first be released by the digestive juices in the gastrointestinal tract (GI tract) to be subsequently absorbed (taken up) in the small intestine, primarily in the duodenum (duodenum) and proximal jejunum (upper jejunum). Absorption occurs transcellularly (mass transport through the epithelial cells of the intestine) by an active mechanism following saturation kinetics at low to normal calcium intakes and additionally paracellularly (mass transport through the interstitial spaces of the intestinal epithelial cells) by passive diffusion along an electrochemical gradient at high intakes. Passive intestinal absorption, which occurs throughout the intestinal tract including the colon (large intestine), is not nearly as effective compared to the active resorption mechanism, which is why the total amount absorbed increases in absolute terms with increasing calcium dose, but decreases in relative terms. While active transcellular calcium absorption is regulated by parathyroid hormone (PTH, a peptide hormone synthesized in the parathyroid gland) and calcitriol (physiologically active form of vitamin D3, 1,25-dihydroxylcholecalciferol, 1,25-(OH)2-D3), respectively), passive paracellular diffusion remains unaffected by the hormones listed. The regulation of transepithelial calcium resorption by PTH and calcitriol, respectively, is discussed in more detail below. In enterocytes (cells of the small intestinal epithelium), calcium is bound to a specific calcium-binding carrier (transport) protein called calbindin, which transports calcium through the enterocytes to the basolateral (away from the intestinal) cell membrane. 1,25-(OH)2-D3 leads to receptor-mediated stimulation of intracellular (inside the cell) expression of calbindin. Calcium enters the bloodstream by means of a transmembrane Ca2+-ATPase (transport system operating under energy and adenosine triphosphate (ATP) consumption, respectively) and a Ca2+/3 Na+ exchange carrier (calcium transporter driven by an Na+ gradient). The absorption rate of calcium depends on a variety of factors and varies between 15% and 60%. After infancy, calcium absorption shows the highest effectiveness at puberty (~60%), then decreases to 15-20% in adulthood. The following factors inhibit calcium absorption, including complex formation:

The following factors promote calcium absorption:

  • Simultaneous absorption of calcium with food
  • Distribution over several individual doses a day
  • 1,25-Dihydroxylcholecalciferol (1,25-(OH)2-D3) – stimulates intracellular calbindin synthesis.
  • Easily absorbable sugars, such as lactose (milk sugar).
  • Lactic acid
  • Citric acid
  • Amino acids
  • Casein phosphopeptides
  • Non-absorbable carbohydrates, such as inulin, fructooligosaccharides and lactulose, which are bacterially fermented to short-chain fatty acids in the ileum (lower small intestine) and colon (large intestine) → the resulting drop in pH in the intestinal lumen leads to an increased release of bound calcium, leaving more free calcium available for passive absorption

During pregnancy, calcium absorption is increased – mediated by PTH and calcitriol, respectively – to accommodate the daily transfer of calcium across the placenta (placenta) to the fetus (unborn child), which averages 250 mg in the 3rd trimester (third trimester of pregnancy). In addition to the increased intestinal (gut-related )calcium absorption, the additional requirement of the pregnant woman is met by increased calcium release from the skeleton after the 1st trimester. Compared to pregnant women, calcium losses with milk, which range from 250 to 350 mg/day, are compensated for in lactating women by increased calcium mobilization from bone alone, resulting in 5% bone mass loss after six months of lactation. However, within 6-12 months after weaning, bone restoration occurs regardless of the administration of calcium supplements-assuming calcium intake is adequate.

Transport and distribution in the body

The calcium content of the human body is circa 25-30 g (0.8% of body weight) at birth and about 900-1,300 g (up to 1.7% of body weight) in adulthood. About 99 % of the total body calcium is extracellular (outside the cells) in the skeletal system, including the teeth, where it is stored predominantly in bound form as undissolved calcium phosphate or hydroxyapatite (Ca10(PO4)6(OH)2). In bone, calcium accounts for approximately 39 % of the total mineral content. Only slightly less than 1% of the total body mass of calcium is localized in other body tissues (~ 7 g) and body fluids (~ 1 g). Thus, the intracellular calcium content is 10,000-fold lower than the extracellular calcium content. To maintain the concentration gradient between the extracellular and intracellular calcium, the cell membrane is largely impermeable (impermeable) to calcium under resting conditions. In addition, transmembrane pump or transport systems exist, such as Ca2+-ATPases (Ca2+ transporters operating under ATP consumption) and Ca2+/3 Na+ exchange carriers (Ca2+ transporters driven by an Na+ gradient), which transport calcium out of the cell. In the membranes of the endoplasmic reticulum (ER, richly branched channel system of planar cavities in eukaryotic cells) are specific Ca2+-ATPases, so-called SERCAs (sarco-/endoplasmatic reticulum Ca2+-ATPases), which can both pump calcium from the cytosol into the ER – intracellular storage – and transport the mineral back into the cytosol for cellular functions after stimulation of the cell with appropriate calcium-mobilizing stimuli. Three different calcium fractions can be distinguished in the blood. Ionized, free calcium forms the largest fraction with about 50%, followed by protein- (albumin-, globulin-) bound calcium (40-45%) and calcium complexed with low molecular weight ligands, such as citrate, phosphate, sulfate and bicarbonate (5-10%). Both protein deficiencies and pH shifts affect the ratio of calcium fractions to each other. For example, acidosis (blood pH < 7.35) leads to reduced and alkalosis (blood pH > 7.45) to increased protein binding of serum calcium, resulting in a corresponding increase or decrease in the proportion of free, ionized calcium in serum – by approximately 0.21 mmol/l Ca2+ per pH unit. The ionized free calcium fraction (1.1-1.3 mmol/l) represents the biologically active form and is homeostatically controlled by parathyroid hormone, 1,25-(OH)2-D3, and calcitonin (a peptide hormone synthesized in thyroid C cells) (see below). Thus, total serum calcium concentration is kept constant within a relatively narrow range (2.25-2.75 mmol/l).

Excretion

Calcium is excreted predominantly in urine and feces (stool) and marginally in sweat. The renal (kidney-related) amount of calcium eliminated under normal conditions is less than 4 mg/kg body weight per day or less than 300 mg/day in men and less than 250 mg/day in women.Renal calcium excretion results from glomerular filtration and tubular reabsorption (reabsorption by the renal tubules), which occurs passively in the proximal tubule (main part of the renal tubules) and actively in the distal tubule (middle part of the renal tubules) – controlled by PTH, 1,25-(OH)2-D3 and calcitonin – and accounts for more than 98% of the amount filtered. This illustrates that the kidney plays a crucial role in calcium homeostasis, or the maintenance of a constant serum calcium level. The following factors promote renal calcium excretion:

  • Increase in oral calcium intake, for example, through supplementation (e.g., dietary supplements).
  • Caffeine – in coffee, green and black tea, etc.
  • Sodium – as a component of table salt (sodium chloride, NaCl); for every 2 g of dietary sodium, 30-40 mg of calcium is lost in the urine.
  • Increased protein intake – both animal and vegetable protein; 1 g of protein increases renal calcium excretion by 0.5-1.5 mg
  • Increased phosphate intake – in sausages, processed cheese, soft drinks, etc.; a calcium-phosphate ratio in the diet of 1:1.0-1.2 is considered optimal
  • Increased alcohol intake
  • Chronic acidosis (blood pH < 7.35)

Idiopathic hypercalciuria (unphysiologically high urinary calcium concentration, > 4 mg calcium/kg body weight/day) is due to a genetic abnormality with variable expression in which the cause is unknown – absorptive (affecting the intestine), renal (affecting the kidneys), or nutritional. Individuals with idiopathic hypercalciuria, who are at increased risk for urolithiasis (formation of kidney stones) compared with healthy individuals, show higher salt sensitivity (synonyms: salt sensitivity; saline sensitivity; saline sensitivity) than people at normal risk for kidney stones. Saline and protein restriction leads to normalization of renal calcium excretion in hypercalciuric patients. Calcium secreted (excreted) into the gastrointestinal tract is subject to 85% intestinal reabsorption (reabsorption). The remaining 15% (18-224 mg/day) is lost with feces (stool). Calcium losses with sweat are estimated to be 4-96 mg/day, with obligatory losses ranging from 3 to 40 mg/day.

Hormonal regulation of calcium homeostasis

Because calcium plays a central role in a number of vital functions in the human organism, maintenance of extracellular ionized free calcium concentration is essential. Ionized free serum calcium is interrelated with the different calcium compartments – bone, small intestine, kidney – and is kept constant within narrow limits by a complex hormonal regulatory system. The following hormones are involved in the regulation of calcium metabolism:

  • Parathyroid hormone
  • Calcitriol (1,25-dihydroxylcholecalciferol, 1,25-(OH)2-D3)
  • Calcitonin

The hormones listed affect intestinal calcium absorption, renal calcium excretion, and calcium release or uptake into bone. In the case of minor deviations of the extracellular free calcium concentration, the intestinal and renal compensatory mechanisms are usually sufficient. It is only when these regulatory mechanisms fail that calcium is released from the skeleton, resulting in a loss of bone mass associated with a weakening of the mechanical stability of the bone. Changes in extracellular free calcium concentration are sensed by specific membrane proteins called calcium sensors, which belong to the superfamily of G-protein-coupled 7-fold membrane-permeable receptors. Calcium-specific receptors are mainly expressed by parathyroid cells, which release PTH in a calcium-dependent manner, by thyroid C cells, which secrete calcitonin in a calcium-dependent manner, and by renal cells, which synthesize the active 1,25-(OH)2-D3 in a calcium-dependent manner. In addition, calcium sensors can also be detected on a number of other cell types, such as osteoclasts (bone resorbing cells) and enterocytes (intestinal epithelial cells). It is assumed that via the calcium-sensitive receptors a calcium-dependent modulation (increase) of the effect of the hormones PTH, calcitriol and calcitonin takes place at the level of the target cells – bone, small intestine, kidney cells.Extracellular free calcium concentration low – parathyroid hormone and calcitriol.

When serum calcium levels fall – as a result of inadequate intake or increased losses – PTH is increasingly synthesized (formed) in parathyroid cells and secreted (secreted) into the bloodstream. PTH reaches the kidney, where it stimulates the expression of 1-alpha-hydroxylase and thus the synthesis of 1,25-(OH)2-D3, the biologically active form of vitamin D. At the bone, PTH and 1,25-(OH)2-D3 stimulate the activity of osteoclasts, which lead to resorption (breakdown) of bone substance. Calcium is subsequently released from bone and released into the extracellular space. Since calcium is stored in the skeletal system in the form of hydroxyapatite (Ca10(PO4)6(OH)2), phosphate ions are mobilized from bone at the same time – close correlation (relationship) of calcium and phosphate metabolism. At the brush border membrane of the proximal small intestine, calcitriol promotes both active transcellular calcium absorption and phosphate reabsorption and transport of calcium and phosphate into the extracellular space. In the kidney, PTH increases tubular calcium reabsorption while inhibiting tubular phosphate reabsorption. Finally, there is increased renal excretion of phosphate, which has increased accumulation due to mobilization of calcium phosphate from bone and reabsorption from the intestine. The decrease in serum phosphate level, on the one hand, prevents precipitation of calcium phosphate in tissues and, on the other hand, stimulates calcium release from bone – in favor of serum calcium concentration. The result of the effects of PTH and calcitriol on intercompartmental calcium movements at low serum calcium levels is an increase and normalization of extracellular free calcium concentration, respectively. Prolonged elevated 1,25-(OH)2-D3 serum levels lead to inhibition of PTH synthesis and proliferation (growth and proliferation) of parathyroid cells – negative feedback. This mechanism proceeds via the vitamin D3 receptors of parathyroid cells. If calcitriol occupies these receptors specific to itself, the vitamin can influence the metabolism of the target organ. Extracellular free calcium concentration high – calcitonin

An increase in extracellular ionized calcium causes thyroid C cells to synthesize and secrete (secrete) more calcitonin. Calcitonin inhibits the activity of osteoclasts on the bone and thus the breakdown of bone tissue, which promotes calcium deposition in the skeleton. At the same time, the peptide hormone stimulates renal calcium excretion. Through these mechanisms, calcitonin leads to a decrease in serum calcium concentration. Calcitonin represents a direct antagonist (opponent) to PTH. Thus, when extracellular free calcium is increased, the synthesis and secretion of PTH from the parathyroid gland and PTH-induced renal 1,25-(OH)2-D3 production are decreased. This results in decreased mobilization of calcium phosphate from bone, reduced intestinal calcium reabsorption, and decreased tubular calcium reabsorption, and thus increased renal calcium excretion. The result, consistent with the mechanism of action of calcitonin, is a decrease in extracellular free calcium concentration and normalization of serum calcium levels.

Calcium balance

Calcium balance is dependent on age. During the growth phase in childhood and adolescence, assuming adequate calcium intake, there is a positive calcium balance, with more calcium absorbed by the body than eliminated by the kidneys and intestines. The increased activity of osteoblasts (bone-forming cells) leads to increased storage of calcium in the bone substance and thus to increased calcium storage. The maximum bone mineral mass or peak bone density is predominantly acquired during adolescence and young adulthood. Thus, girls and women respectively have about 90 % of the total skeletal mineral content by the age of 16.9 ± 1.3 years and about 99 % by the age of 26.2 ± 3.7 years. In boys and men, respectively, a delay of about 1.5 years can be observed. As a rule, peak bone mass is reached by about the age of 30.The bone mineral content only inadequately characterizes the actual bone strength. Rather, it is determined by factors such as physical activity, muscle mass, body build and size. From the age of 30, there is an equilibrium calcium balance over several decades of life, with the amount of calcium absorbed by the body correlating with the amount of calcium excreted renally and fecally. For example, with a calcium intake of 1,000 mg, approximately 200 mg is absorbed and about 200 mg is eliminated by the kidneys, while 250-500 mg is released from bone and reabsorbed as part of remodeling processes. To prevent the calcium balance from becoming negative, care should be taken to ensure adequate dietary calcium intake. Despite a balanced calcium metabolism, bone density decreases continuously from the age of 30. In healthy people, the loss of bone mineral mass is about 1% per year. The cause of bone mass loss with increasing age is the increased activity of osteoclasts (bone-degrading cells), which is accompanied by increased breakdown of bone tissue and increased calcium release from bone. Finally, more calcium is excreted in the urine and feces than is absorbed by the small intestine and bone. Elderly people therefore have a negative calcium balance. In particular, bone mass progressively decreases in postmenopausal women (menopause; menopause in women) due to the altered estrogen status. As a result of studies, an onset of loss of bone and mineral substance could be observed in females at the femoral neck from the age of 37 and at the spine from the age of 48. Postmenopausal women are therefore at increased risk of developing osteoporosis (bone loss). The lower the “peak bone mass”, the higher the risk of osteoporosis. Studies in postmenopausal women have shown that the level of oral calcium intake is closely linked to the risk of hip fractures. Calcium administration of 800-1,000 mg/day resulted in reduced osteoclast activity in the subjects, which halted bone resorption or bone mass loss and reduced fracture incidence.