The regulation of calcium concentration in the blood is crucial, and shifts in blood calcium concentration above or below a narrow range can cause serious problems. When blood calcium falls below this range, the nervous system becomes overly excited, resulting in muscle spasms and even seizures. When blood calcium rises above this range, the nervous system becomes depressed and muscles—including the heart—weaken. Regulation of blood calcium is difficult because only about 0.1 percent of the calcium in the body is located in the extracellular fluid. About 1 percent is in cells, and almost 99 percent is in the bones. Therefore the body must maintain a tiny pool of calcium in the blood at a precise concentration, and that tiny pool can be influenced greatly by relatively small shifts in the much larger pools of calcium in the cells and bones.

The body has multiple mechanisms for changing blood calcium levels, including:

These mechanisms are controlled by three hormones: calcitonin, parathyroid hormone, and calcitriol (synthesized from vitamin D).

CALCITONIN REDUCES BLOOD CALCIUM Calcitonin is released by the thyroid and lowers the concentration of calcium in the blood, mainly by regulating bone turnover (Figure 40.13). Bone is continuously remodeled through a dynamic process that involves both resorption of old bone and synthesis of new bone, as we will discuss in Key Concept 47.3. Cells called osteoclasts break down bone and release calcium into the blood, and cells called osteoblasts take up calcium from the blood and deposit it in new bone. Calcitonin decreases the activity of osteoclasts and thereby favors removal of calcium from the blood and its deposition in bone by osteoblasts. The turnover of bone in adult humans is not very high, so calcitonin does not play a major role in calcium homeostasis in adults. It is probably more important in young individuals whose bones are actively growing.

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PARATHYROID HORMONE INCREASES BLOOD CALCIUM The parathyroid glands are four tiny structures embedded in the posterior surface of the thyroid gland (see Figure 40.13). Their single hormone product, parathyroid hormone (PTH, also called parathormone), is the most important hormone in the regulation of blood calcium levels. Circulating calcium activates receptors in the cell membrane of the parathyroid cells. When these receptors are active, they inhibit the synthesis and release of PTH. A fall in blood calcium removes this inhibition and triggers the synthesis and release of PTH. PTH stimulates bone turnover by actions on both osteoclasts and osteoblasts. The end result of these actions of PTH is a net increase of calcium in the blood. PTH also maintains blood concentration of calcium by stimulating the kidneys to reabsorb it rather than excrete it in the urine.

CALCITRIOL INCREASES BLOOD CALCIUM It had long been known that fragile bones were common among people living at high latitudes, where winter days are short and the winter diet often lacks fish, dairy products, and fresh vegetables. Since the condition could be reversed by taking cod-liver oil, it was assumed that a vitamin deficiency was involved. That vitamin was named vitamin D, but when its chemical identity was established, this molecule turned out not to be a vitamin at all.

A vitamin is a substance that the body requires in small quantities but cannot synthesize for itself and must therefore obtain from food (or from supplements such as vitamin pills). However, vitamin D—now more accurately named calciferol—is synthesized naturally from cholesterol when skin cells receive ultraviolet light. Calciferol is not an active hormone, but through actions of the liver and kidneys it is converted into the active form called calcitriol, which circulates in the blood and acts on distant cells (and therefore is a hormone). The conversion of calciferol to calcitriol is activated by PTH. Calcitriol promotes the absorption of calcium from food in the gut. Thus the combined actions of PTH and calcitriol raise blood calcium levels.