Calcium is necessary for muscle contraction, blood coagulation, enzyme activity, neural conduction and neuromuscular transmission, glycogen metabolism, vascular smooth muscle tone, cell growth and division, hormone release, membrane permeability and stability, skeletal structure, and many other functions.
Calcium acts, and is maintained, in both the intracellular and extracellular spaces. Within each space, the calcium is in either an insoluble or soluble form. Soluble extracellular calcium (calcium measured in serum or plasma) is divided into three fractions: ionized, complexed, and protein bound.
Ionized calcium is the free, biologically active form and accounts for 55% of total serum calcium, while roughly 35% is protein bound and 10% is complexed. The skeleton serves as a reservoir for calcium and phosphate ions and contains 99% of the total body insoluble extracellular calcium. Intracellular calcium comes from the extracellular space and is maintained in low concentrations.
Flows of calcium into and out of the body and between body compartments, such as the skeleton and extracellular space, are controlled by homeostatic hormones and specialized cells. The major hormones in control of calcium balance are parathyroid hormone, calcitonin, and calcitriol; see on regulators of calcium homeostasis. Other hormones, such as corticosteroids, estrogens, thyroxine, somatotropic hormone, growth hormone, glucagon, and prolactin, have been found to contribute to the maintenance of calcium metabolism.
The goal of calcium homeostasis is to maintain a normal level of extracellular calcium. Serum ionized calcium (iCa) is the fraction of calcium that has biologic activity and is tightly regulated so there is little variability in the concentration. Regulation occurs primarily via intestinal and renal handling of calcium to maintain homeostasis when minor calcium demands occur; however, if there is a more severe hypocalcemic event, calcium is mobilized from the skeletal system.
Parathyroid Hormone in Calcium Regulation in Dogs and Cats
Most animals have four parathyroid glands, though the actual number of glands can vary. The parathyroid glands are located either external to the thyroid capsule or within the capsule. Parathyroid glands may be ectopic, located anywhere from the base of the tongue to the mediastinum. They are normally small, ranging in size from 2 to 4 mm; they may be difficult to detect and can easily be mistaken for thyroid cysts or nodules.
The parathyroid glands generate, store, and secrete a calcium-regulating hormone called parathyroid hormone (PTH). Parathyroid hormone is made autonomously and stored within the gland’s cells. Special calcium-sensing receptors reside within the chief cells of the parathyroid glands and send signals to either increase or decrease PTH synthesis and release.
PTH is secreted in response to decreased extracellular calcium concentrations; secretion is stopped in response to increased extracellular calcium concentrations. Once released, PTH has a short half-life of 3–5 minutes. The relationship between PTH and ionized calcium concentrations is sigmoidal; ie, very small changes in calcium result in large changes in PTH.
Parathyroid hormone has three target organs: kidney, gastrointestinal tract, and bone.
Parathyroid hormone acts directly on the kidney to increase renal excretion of phosphorus and reabsorption of calcium, and to synthesize calcitriol. Elevated concentrations of calcitriol stimulate intestinal absorption of calcium and phosphate. PTH can increase osteoclast numbers, stimulate osteoclast function, increase bone resorption, and bind to osteoblasts to increase calcium and phosphorus mobilization into the extracellular fluid. Inhibition of PTH occurs with increased extracellular calcium concentrations.
Calcium-sensing receptors provide negative feedback to the chief cells. Calcitriol also binds to vitamin D receptors (VDRs) in the parathyroid cells to provide negative feedback.
Parathyroid hormone-related protein (PTHrP) is a normal hormone produced in the body; however, it can also be produced by some tumors, resulting in a paraneoplastic hypercalcemia. PTHrP can bind to and activate PTH receptors, resulting in increased extracellular calcium.
Vitamin D in Calcium Regulation in Dogs and Cats
The role of vitamin D compounds or metabolites has not been fully investigated or understood in dogs with primary hyperparathyroidism (PHPT). Vitamin D of plant origin is called ergocalciferol or vitamin D2, and cholecalciferol or vitamin D3 is synthesized in the skin or from animal tissue. These calciferols are bound to a vitamin D binding protein (VDBP), which transports the prohormone to the liver for bioactivation by hydroxylation to calcidiol.
Calcidiol, which is 25(OH) vitamin D, can be measured in the serum and is used to assess the vitamin D status of a patient. Calcidiol then goes to the kidney, where it interacts with 1-alpha-hydroxylase creating calcitriol, the most biologically active metabolite of vitamin D.
Calcitriol increases calcium and phosphorus absorption in the gastrointestinal tract and can also act to increase calcium and phosphorus reabsorption in the kidney. Calcitriol aids in normal bone development.
Calcitonin in Calcium Regulation in Dogs and Cats
Calcitonin is synthesized in the C cells of the thyroid, and it functions in calcium homeostasis. It is secreted autonomously and will increase with hypercalcemia; however, its effects on calcium homeostasis are not strong. Calcitonin acts on the bone to inhibit osteoclast activity and number. It has also been found to decrease renal tubular resorption of phosphorus. The net effect of calcitonin is decreased serum calcium and phosphorus.
The primary regulators of calcium homeostasis are PTH, calcitriol, calcitonin, and extracellular calcium concentration.
The target organs involved in calcium homeostasis are kidney, bone, and intestine.