Calcium: the key to many human functions

Calcium: the key to many human functions

Calcium is the most abundant inorganic element in the human body and is an essential key for many physio-logical processes. Ca²⁺ has numerous intra and extracellular physiological roles, for example, a universal role as messenger and mediator for cardiac, skeletal and smooth muscle contractions. Calcium ions are a critical factor in several life-defining biochemical processes as well as in the endocrine, neural and renal aspects of blood pressure homeostasis.

Calcium has the symbol Ca and atomic number 20 and is a soft grey alkaline earth metal. Calcium has four stable isotopes (⁴⁰Ca and ⁴²Ca–⁴⁴Ca) and the metal reacts with water with the formation of calcium hydroxide and hydrogen.

2Ca + 2H₂O → 2CaOH + H₂                       (3.3)

Calcium salts can be found in everyday life. Limestone, cement, lime scale and fossils are only a few examples where we encounter Ca²⁺. They also have a wide spectrum of applications spanning from insecticides to clinical applications. Calcium arsenate [Ca₃(AsO₄)₂] is extremely poisonous and is used in insecticides. Calcium carbonate (CaCO₃) can be found in clinical applications such as antacids, but note that an excessive intake can be hazardous. Calcium chloride (CaCl₂) is used in ice removal and dust control on dirt roads, as a conditioner for concrete and as an additive in canned tomatoes. Calcium cyclamate [Ca(C₆H₁₁NHSO₄)₂] is used as a sweetening agent, and calcium gluconate [Ca(C₆H₁₁O₇)₂] is used as a food additive in vitamin pills. Calcium hypochlorite Ca(OCl)₂ can be found in swimming pool disinfectants, in bleaching agents, in deodorants and in fungicides. Calcium permanganate [Ca(MnO₄)₂] is used in textile production, as a water-sterilising agent and in dental procedures. Calcium phosphate [Ca₃(PO₄)₂] finds applications as a supplement for animal feed, as a fertiliser, in the manufacture of glass and in dental products. Calcium sulfate (CaSO₄⋅2H₂O) is the common blackboard chalk.

Biological importance

Calcium ions play important roles in the human body in a variety of neurological and endocrinological processes. Calcium is known as a cellular messenger and it has a large intra- versus extracellular gradi-ent (1 : 10 000), which is highly regulated by hormones. This gradient is necessary to maintain the cellular responsiveness to diverse extracellular stimuli. Calcium ions are also involved in the formation of bones and teeth, which act also as a reservoir for calcium ions.

A normal adult body contains ∼1000 g of calcium, of which around 99% are extracellular and most of which is stored in bones and teeth. Bones actually serve as a dynamic store for Ca²⁺. The remaining 1% of Ca²⁺ can be found in the extracellular space, such as plasma, lymph and extracellular water. The intra and extracellular Ca²⁺ concentration is extremely important to many physiological functions and is therefore rigorously controlled (Figure 3.7) .

Calcium ions are regulated within the gut, skeleton and kidneys. The Ca²⁺ homeostasis is normally in equi-librium, which means that the amount of Ca²⁺ enters the body is equal to the amount of Ca²⁺ leaving the body. Calcium ion levels are regulated by hormones that are not regulated by the Ca²⁺ level, called noncalciotropic hormones, for example, sex hormones and growth factors. In contrast, there are hormones that are directly related to Ca²⁺, for example, PTH (parathyroid hormone), which are called calciotropic hormones. PTH con-trols the serum plasma level of Ca²⁺ by regulating the re-absorption of Ca²⁺ in the nephron, stimulating the uptake of Ca²⁺ from the gut and releasing Ca²⁺ from the bones which act as a reservoir.

Modified hydroxylapatite, also frequently called hydroxyapatite and better known as bone mineral, makes up ∼50% of our bones. Hydroxylapatite is a natural form of the mineral calcium apatite, whose formula is usually denoted as Ca₁₀(PO₄)₆(OH)₂. Modifications of hydroxylapatite can also be found in the teeth, and a chemically identical substance is often used as filler for replacement of bones, and so on. Nevertheless, despite similar or identical chemical compositions, the response of the body to these compounds can be quite different.

How does dietary calcium intake influence our lives?

It is believed that an optimal dietary calcium intake can prevent chronic diseases. In the Stone Age, the average calcium intake was 2000–3000 mg Ca²⁺/day per adult, whereas now-a-days it has decreased to an average of 600 mg/day . This means that we are living in permanent calcium deficiency, and it is believed that there are linkages to various chronic diseases, such as bone fragility, high blood pressure and colon cancer .

Ca²⁺ is an essential nutrient, and the required amount varies throughout a person’s life time depending on the stage of life. There have been three stages of life identified when the human body needs an increased level of Ca²⁺. The first one is childhood and adolescence because from birth to the age of ∼18 the bones form and grow until they reach their maximum strength. Pregnancy and lactation has also been identified as a time when the human body is in need of an increased level of Ca²⁺. A full infant accumulates around 30 g of Ca²⁺ during gestation and another 160–300 mg/day during lactation. Ageing has been identified as the third period of life in humans when increased calcium intake is required. This has been associated with several changes to the calcium metabolism in the elderly (Table 3.2).

Calcium deficiency: osteoporosis, hypertension and weight management

Osteoporosis is most commonly associated with calcium deficiency, but an adequate calcium intake should not only be considered as a therapy for bone loss. It should be seen as an essential strategy for the maintenance of health in the ageing human. Ninety-nine percent of Ca2+ is found in the bones, as they function as a reservoir.

 Osteoporosis is known to be the major underlying cause on bone fractures in postmenopausal women. Calcium uptake and plasma concentrations are closely regulated by hormones, as outlined in previous Section . Nevertheless, there has been no clear and direct relationship between Ca²⁺ intake and bone health established until now. It is believed that a high Ca²⁺ concentration and vitamin D level is essential in the first three decades of life in order to establish an optimum bone density level. These also modify the rate of bone loss, which is associated with ageing.

Studies support the hypothesis that calcium supplementation can reduce blood pressure, being more ben-eficial to salt-dependent hypertension. The regulation of the cellular calcium metabolism is central to blood pressure homeostasis. It is believed that the higher the level of cytosolic-free calcium ions, the greater the smooth muscle vasoconstrictor tone, which in turn has an effect on the sympathetic nervous system activity and thus on the blood pressure. Nevertheless, studies do not justify the use of calcium supplementation as the sole treatment for patients with mild hypertension.

It has been hypothesised that there exists a link between dietary calcium and weight management in humans. It has been proposed that a low-calorie, high-Ca²⁺ diet helps in supporting the fight against obesity and increase the energy metabolism. The recommended Ca²⁺ intake should be around 1200 mg/day as previously mentioned depending on the age. Available evidence indicates that increasing the calcium intake may sub-stantially reduce the risk of being overweight, although long-term, large-scale prospective clinical trials need to be conducted to confirm or better clarify this association.

Renal osteodystrophy

Renal osteodystrophy, also called renal bone disease, is a bone mineralisation deficiency seen in patients with chronic or end-stage renal failure.

Vitamin D is usually activated in the liver to the pro-hormone calcidiol and then in the kidney to calcitriol, which is the active form of vitamin D. Both activation steps are based on a hydroxylation reaction. Pro-vitamin D is hydroxylated in the 25 position in the liver (calcidiol) and then in the kidney at the 1α-position (calcitriol). Calcitriol helps the body to absorb dietary Ca²⁺ (Figure 3.8).

In patients with renal failure, the activation to calcitriol is depressed, which results in a decreased con-centration of Ca²⁺ in the blood plasma. Furthermore, the plasma phosphate level increases as a result of the kidney impairment. This, in turn, reduces the amount of free Ca²⁺ in the blood even more, as the phosphate complexes the free Ca²⁺. The pituitary gland senses the low levels of plasma Ca²⁺ and releases PTH. As previously outlined, PTH increases the re-absorption of Ca²⁺ in the nephron and absorption in the gut, and promotes the release of Ca²⁺ from the bones. In turn, this leads to a weakening of the bone structure.

Patients can be treated with phosphate binders in order to avoid excess phosphate absorption from the gut. Dialysis will also be helpful in removing excess phosphate from the blood. Furthermore, the patient can be given synthetic calcitriol and potentially calcium supplements.

Kidney stones

Around 20–40% of all kidney stones are associated with elevated Ca²⁺ level in the urine. For a long time, it has been suggested that low dietary calcium intake would be the best method to prevent the recurrence of kidney stones. More recent studies involving patients who suffered from recurring calcium oxalate stones showed that a low calcium diet did not prevent the formation of kidney stones. It was actually found that a higher calcium intake of around 1200 mg/day resulted in a significant reduction of the recurrence of kid-ney stones by around 50%. It is believed that the restriction of calcium leads to an increase in absorption and excretion of oxalate in the urine and therefore promotes the formation of calcium oxalate stones. Cur-rently, the conclusion is that kidney stone formation in healthy individuals is not associated with calcium supplementation .

Clinical application

Calcium supplements are usually required only if the dietary Ca²⁺ intake is insufficient. As previously men-tioned, the dietary requirements depend on the age and circumstances; for example, an increased need can be seen in children, in pregnant women and in the elderly where absorption is impaired. In severe acute hypocalcaemia, a slow i.v. injection of a 10% calcium gluconate has been recommended. It has to be kept in mind that the plasma Ca²⁺ level and any changes to the electrocardiogram (ECG) have to be carefully monitored .

A variety of calcium salts are used for clinical application, including calcium carbonate, calcium chloride, calcium phosphate, calcium lactate, calcium aspartate and calcium gluconate. Calcium carbonate is the most common and least expensive calcium supplement. It can be difficult to digest and may cause gas in some people because of the reaction of stomach HCl with the carbonate and the subsequent production of CO₂ (Figure 3.9).

CaCO3 + 2HCI → CO2 + CaCl2 + H2O

Figure 3.9 Chemical equation showing the synthesis of CO2 under acidic stomach conditions

Calcium carbonate is recommended to be taken with food, and the absorption rate in the intestine depends on the pH levels. Taking magnesium salts with it can help prevent constipation. Calcium carbonate consists of 40% Ca²⁺, which means that 1000 mg of the salt contains around 400 mg of Ca²⁺. Often, labels will only indicate the amount of Ca²⁺ present in each tablet and not the amount of calcium carbonate (Figure 3.10).

Calcium citrate is more easily absorbed (bioavailability is 2.5 times higher than calcium carbonate); it is easier to digest and less likely to cause constipation and gas than calcium carbonate. Calcium citrate can be taken without food and is more easily absorbed than calcium carbonate on an empty stomach. It is also believed that it contributes less to the formation of kidney stones. Calcium citrate consists of around 24% Ca²⁺, which means that 1000 mg calcium citrate contains around 240 mg Ca²⁺. The lower Ca²⁺ content together with the higher price makes it a more expensive treatment option compared to calcium carbonate, but its slightly different application field can justify this (Figure 3.11).

The properties of calcium lactate are similar to those of calcium carbonate , but the former is usually more expensive. Calcium lactate contains effectively less Ca²⁺ per gram salt than, for example, calcium carbonate. Calcium lactate consists of only 18% Ca²⁺, making it a less ‘concentrated’ salt (Figure 3.12) .

Calcium gluconate is prescribed as a calcium supplement, but it is also used in the urgent treatment of hyperkalaemia (K⁺ plasma levels above 6.5 mmol/l). Hyperkaleamia in the presence of ECG changes usually requires immediate treatment, and a 10% calcium gluconate solution intravenously administered is recommended. Administration of the calcium solution does not lower the plasma K⁺ level but protects temporarily against myocardial excitability and therefore temporarily reduces the toxic effects of hyperkalaemia. Calcium gluconate contains effectively the least Ca²⁺ per amount of supplement (only around 9%). That means that in 1000 mg calcium gluconate, only 90 mg is actual Ca²⁺ (Figure 3.13).

Side effects

Several large long-term studies have shown that a daily intake of 1000–2500 mg of calcium salts is safe. Side effects have been observed only at relatively high doses, being manifested in GI disturbances such as constipation and bloating and, in extreme cases, arrhythmia . The GI system normally adjusts after a while, and problems should resolve themselves. Calcium salts are generally better absorbed in an acid environment, so patients with a low production of stomach acid or elderly patients who are on high doses of antiulcer medication might experience problems with absorption. It is then recommended to consume the calcium supplement with a meal .

Nevertheless, it is important to note that calcium ions can interfere with the absorption of some drugs, such as antibiotics. For example, tetracycline and quinolone antibiotics can chelate Ca²⁺ ions and form complexes which cannot be absorbed anymore. Therefore, calcium supplements and antibiotics should not be taken together. Patients are typically advised to take antibiotics 1 h before or 2 h after food .