Merck Manual

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Professional Version

Calcium Physiology and Calcium-regulating Hormones


Mark E. Peterson

, DVM, DACVIM-SAIM, Animal Endocrine Clinic, New York

Reviewed/Revised Jul 2013 | Modified Oct 2022

The concentration of calcium in the blood of mammals is ~10 mg/dL, with some variation due to species (eg, as much as 13 mg/dL is normal in horses and rabbits), age, dietary intake, and analytic method. Calcium in plasma or serum exists in three forms or fractions: 1) Protein-bound calcium accounts for approximately one-third of the total serum calcium concentration. Protein-bound calcium cannot diffuse through membranes and thus is not usable by tissues. 2) Ionized or free calcium is the physiologically active form that accounts for 50%–60% of total calcium concentration. 3) Complexed or chelated calcium is bound to phosphate, bicarbonate, sulfate, citrate, and lactate and accounts for ~10% of the total calcium concentration.

The calcium ion is an essential structural component of the skeleton and plays a key role in muscle contraction, blood coagulation, enzyme activity, neural excitability, secondary messengers, hormone release, and membrane permeability. Precise control of calcium ion in extracellular fluids is vital to health. Three major hormones (PTH, vitamin D, and calcitonin) interact to maintain a constant concentration of calcium, despite variations in intake and excretion. Other hormones, such as adrenal corticosteroids, estrogens, thyroxine, somatotropin, and glucagon, may also contribute to the maintenance of calcium homeostasis.

Parathyroid Hormone:

PTH is synthesized and stored in the chief cells of the parathyroid glands. Synthesis is regulated by a feedback mechanism involving the level of blood calcium (and, to a lesser degree, that of magnesium). In addition, biological amines, peptides, steroids, and several classes of drugs can influence PTH secretion.

The primary function of PTH is to control calcium concentration in the extracellular fluid, which it does by affecting the rate of transfer of calcium into and out of bone, resorption in the kidneys, and absorption from the GI tract. The effect on the kidneys is the most rapid, causing reabsorption of calcium and excretion of phosphorus. The major initial effect on bone is to mobilize calcium from the bone to the extracellular fluid; later, bone formation may be enhanced. PTH does not directly affect calcium absorption from the gut. Its effect is mediated indirectly by regulation of synthesis of the active metabolite of vitamin D.

Vitamin D:

The second major hormone involved in the regulation of calcium metabolism and skeletal remodeling is vitamin D, which includes cholecalciferol (vitamin D3) of animal origin, as well as ergocalciferol (vitamin D2) of plant origin. Vitamin D has long been considered an essential dietary ingredient, but in several species, including sheep, cattle, horses, pigs, and people, vitamin D can be formed in the skin from a cholesterol metabolite (7-dehydrocholesterol) after exposure to ultraviolet light. In contrast, dogs and cats are not able to synthesize vitamin D3 adequately in the skin and mainly depend on dietary intake.

Vitamin D must be metabolically activated before it can function physiologically. The biologic actions of vitamin D depend on hydroxylation in the liver and kidneys to form the biologically active 1,25-dihydroxyvitamin D (calcitriol). This conversion in the kidneys is the rate-limiting step in vitamin D metabolism, and it is partly responsible for the delay between vitamin D administration and expression of its biologic effects. PTH and conditions that stimulate its secretion, as well as hypophosphatemia, increase the formation of the active vitamin D metabolite. High circulating phosphorus concentrations have the opposite effect. Under certain conditions, prolactin, estradiol, placental lactogen, and possibly somatotropin have a similar enhancing effect. Increased secretion of these hormones, either alone or in combination, appears to be important in the efficient adaptation to the major calcium demands of pregnancy, lactation, and growth.


Calcitonin is a 32-amino acid polypeptide hormone secreted by the parafollicular cells (C-cells) of the thyroid gland in mammals and by ultimobranchial tissue in avian and other nonmammalian species. The concentration of calcium ion in extracellular fluids is the principal stimulus for the secretion of calcitonin by C-cells. In hypercalcemia, the rate of secretion of calcitonin is increased greatly by rapid discharge of stored hormone from C-cells into interfollicular capillaries. Hyperplasia of C-cells occurs in response to longterm hypercalcemia. When blood calcium is lowered, the stimulus for calcitonin secretion is diminished. The storage of large amounts of preformed hormone in C-cells and rapid release in response to a moderate rise in circulating calcium probably reflect the physiologic role of calcitonin as an “emergency” hormone to protect against development of hypercalcemia.

Calcitonin exerts its effects by interacting with target cells, primarily in bone and kidney. The actions of PTH and calcitonin are antagonistic on bone resorption but synergistic on decreasing the renal tubular reabsorption of phosphorus. The hypocalcemic effects of calcitonin are primarily the result of decreased entry of calcium from the skeleton into plasma, resulting from a temporary inhibition of PTH-stimulated bone resorption. The hypophosphatemia develops from a direct action of calcitonin, which increases the rate of movement of phosphorus out of plasma into soft tissue and bone and inhibits the bone resorption stimulated by PTH and other factors. Although many effects have been attributed to calcitonin at pharmacologic doses, their physiologic relevance is suspect. Physiologically, calcitonin has at best a minor role in regulating blood concentrations of calcium. Neither chronically high (eg, as in animals with medullary thyroid cancer) nor chronically low (eg, as in animals after surgical removal of the thyroid gland) circulating calcitonin concentrations result in any changes in the serum calcium concentration.

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