Calcium homeostasis refers to the regulation of the concentration of calcium ions in the extracellular fluid [Ca++]ECF. This parameter is tightly controlled because the calcium ions have a stabilizing effect on voltage-gated ion channels. For instance, when [Ca++]ECF is too low (hypocalcemia), voltage-gated ion channels start opening spontaneously, causing nerve and muscle cells to become hyperactive. The syndrome of involuntary muscle spasms due to low [Ca++]ECF is called hypocalcemic tetany. Conversely, when [Ca++]ECF is too high (hypercalcemia), voltage-gated ion channels don't open as easily, and there is depressed nervous system function. Another problem of hypercalcemia is that calcium can combine with phosphate ions, forming deposits of calcium phosphate (stones) in blood vessels and in the kidneys.
The figure above illustrates the physiological influences on [Ca++]ECF.
[Ca++]ECF is influenced by dietary intake,
Ca++ absorption in the small intestine, and by
excretion of Ca++ in the urine. Importantly, the
bones contain 99% of the Ca++ in the body, so bones
provide a reservoir of Ca++ that can be used to
The two most important hormones for maintaining calcium levels in the body are parathyroid hormone (PTH) and 1,25(OH)2D (the active form of vitamin D). The major regulator is PTH, which is part of a negative feedback loop to maintain [Ca++]ECF (see Humoral regulation). PTH secretion is stimulated by hypocalcemia, and it works through three mechanisms to increase Ca++ levels:
PTH has a rapid effect (occurring within minutes), whereby it stimulates osteoblasts to pump Ca++ ions out of the fluid surrounding the bone (which has a higher Ca++ concentration) and into the ECF. Over a longer time course, PTH stimulates bone resorption by stimulating osteoclastogenesis. Although PTH stimulates bone resorption, it is actually the osteoblasts that express PTH receptors. PTH stimulation of osteoblasts causes them to express a signaling molecule that activates osteoclasts. For more details, see the page on Bone remodeling.
PTH has two important effects on the kidney that work to increase [Ca++]ECF. First, it decreases the loss of Ca++ ions in the urine by stimulating Ca++ reabsorption. "Reabsorption" is the term used to describe the transfer of substances from the forming urine back into the ECF. Filtration, the first step in urine formation, is a nonspecific process, whereby water and low molecular weight substances move by bulk flow from the plasma and into the forming urine. Reabsorption, which is performed by the cells of the kidney tubules, allows the recovery of those useful small molecules such as glucose, amino acids, and Ca++ ions. As well as stimulating Ca++ reabsorption, PTH also inhibits phosphate reabsorption in the kidney.
The other key effect of PTH on the kidney is to stimulate production of 1,25(OH)2D, the active form of vitamin D. A precursor (known specifically as vitamin D3 or cholecalciferol) is synthesized in a photochemical reaction in the skin, in response to sunlight. Cholecalciferol is then chemically modified in the liver to form 25-(OH)D (this also happens to a similar compound that is present in foods) . The enzyme in the liver is constitutively active, meaning it is always working. By contrast, the kidney enzyme is regulated. The role of PTH is to stimulate the regulated kidney enzyme, resulting in the production of 1,25(OH)2D. This is extremely important for bone health and Ca++ homeostasis because 1,25(OH)2D works in the small intestine to promote Ca++ absorption.
In kidney disease, inadequate amounts of 1,25(OH)2D are made. What happens is that Ca++ homeostasis is maintained at the expense of bone. [Ca++]ECF drops because of a lack of Ca++ absorption from the diet. Hypocalcemia stimulates high levels of PTH secretion; this is termed secondary hyperparathyroidism because the problem that causes the hyperparathyroidism is in the kidney, not at the parathyroid gland. Secondary hyperparathyroidism is treated by administering vitamin D and Ca++ supplements. The drug cinacalcet is approved for the treatment of secondary hyperparathyroidism. Cinacalcet is a calcimimetic drug that binds to the Ca++ receptor on cells in the parathyroid gland, inhibiting the secretion of PTH.