Calcium homeostasis refers to the regulation of the concentration of calcium ions in the extracellular fluid.
An adult body contains about one kilogram of calcium. It is the fifth most abundant element in the human body.
Calcium takes part in a wide range of biologic functions including bone mineralization and. Calcium is mainly provided by diet though some elderly persons also require calcium supplementation.
The amount of required calcium is age dependent. More calcium is required in the growing years.
Intestinal absorption, renal reabsorption, and the rate of bone turnover are the main determinants of calcium requirement. Calcium is regulated by complex interactions of
- Parathyroid hormone
- 1,25-dihydroxyvitamin D [1,25(OH)2D]
- Ionized calcium
Main receptors for these hormones are in the gut, kidney, and bone.
Functions of Calcium
99% of calcium is present in the skeleton as calcium-phosphate complexes, primarily as hydroxyapatite. Calcium provides strength to the bone and also serves as a dynamic store to maintain the intra and extracellular calcium pools.
Calcium which is not present in the bone represents <1% of total body calcium and is in constant and rapid exchange within the various calcium pools. It is responsible for a number of functions which include
- Extra and intracellular signaling voltage-gated sodium ion channels
- Nerve impulse transmission
- Clotting factors functions
In skeletal and heart muscle contraction
Normal serum calcium ranges from 8.8 to 10.4 mg/dl (2.2 to 2.6 mM) in healthy persons. This comprises free ions or Ca+2 form [51%], protein-bound [albumin, globuli] complexes [40%], and ionic complexes 9%].
The major ionic complexes in serum are calcium phosphate, calcium carbonate, and calcium oxalate.
Calcium Balance or Bone Balance
Calcium balance refers to the state of the body stores of calcium at equilibrium over some extended time period which may range from days to months. It is determined by the net effects of intestinal absorption and excretion by kidneys on bone calcium which is the dominant calcium pool.
It also may be referred to as bone balance. It changes throughout life.
For example, children have in positive bone balance because the bone formation is more than bone resorption. Young adults are in neutral bone balance as formation equals resorption. Elderly people have greater bone resorption than formation, therefore, are in negative balance.
Exercise, anabolic drugs and anti-resorptive drugs like bisphosphonate promote bone formation and are associated with increasing bone balance.
Similarly, immobilization, weightlessness, and sex steroid deficiency lead to negative bone balance.
Bone mineral content increases throughout childhood, peaks in adolescence, remains relatively static in early/late adulthood and decreases in old age.
Dietary calcium intake is a major determinant of calcium balance.
Regulation of Calcium Homeostasis
Calcium homeostasis is regulated through interaction of hormones that controls calcium transport in the intestine, kidney, and bone.
Regulators of Calcium Homeostasis
Parathyroid hormone, and 1,25 dihydroxy vitamin D and ionized calcium along with their receptors [ PTH receptors, vitamin D receptors and calcium-sensing receptors or CaR] are responsible for maintaining calcium homeostasis.
The parathyroid hormone is the most important regulator of calcium metabolism. It is a polypeptide consisting of 84 amino acids and is secreted by the chief cells of the parathyroid glands in response to hypocalcemia and hyperphosphatemia.
It carries out following functions
- Stimulates the osteoclasts and causes bone resorption, leading to rise in the serum calcium and phosphorus.
- Stimulates the 1-alpha-hydroxylase enzyme and to cause an increase in 1,25 dihydroxyvitamin D production.
- Increases the reabsorption of calcium in the distal renal tubules, decreasing calcium secretion
- Parathyroid hormone decreases the reabsorption of phosphorus causing increased loss of phosphorus in urine
- Increased levels of parathyroid hormone cause hypercalcemia, hypophosphatemia, and high urinary calcium and phosphorus.
Calcium has a negative feedback effect on the parathyroid glands. Phosphorus has been shown to have a direct stimulatory effect on the parathyroid glands.
Vitamin D is synthesized in the skin but is also present in the diet. The active form is 1, 25 dihydroxyvitamin D. Its main action is to enhance the availability of calcium and phosphorus for new bone formation.
- Vitamin D enhances the intestinal absorption of calcium and phosphorus, increasing their serum levels
- Increases the reabsorption of urinary calcium and phosphorus in the renal tubules.
- Suppresses the vitamin D receptors on the parathyroid glands to suppress PTH secretion.
Calcitonin is produced in by the parafollicular cells (also known as C-cells) of the thyroid. It is an important hormone in calcium and phosphorus metabolism. In many ways, calcitonin has an effect opposite to parathyroid hormone. More specifically, calcitonin lowers blood Ca2+ levels in the following ways:
- Inhibits Ca2+ absorption by the intestines
- Inhibits osteoclast activity in bones
- Stimulates osteoblastic activity in bones.
- Inhibits renal tubular cell reabsorption of Ca2+ allowing it to be excreted in the urine
The calcitonin receptors are, found on osteoclasts, and in the kidney and regions of the brain.
Feed Back Loop of Calcium Metabolism
The aim of calcium homeostasis is to maintain extracellular ionized calcium levels in the physiologic range. This is done by increasing or decreasing calcium dietary calcium absorption and by the flow of calcium to and from essential stores.
A decrease in serum calcium inactivates the calcium-sensing receptors in the parathyroid glands causing an increase in parathyroid hormone secretion.
Parathyroid hormone acts on PTH receptors in the kidney which increases tubular calcium reabsorption. Parathyroid hormone also causes increased bone resorption so that calcium from the skeletal stores could be made available in the blood.
The decrease in serum calcium probably also causes inactivation of the calcium in the kidney to increase calcium reabsorption and potentiate the effect of PTH.
The increased parathyroid hormone also causes the kidney to increase secretion of active form of vitamin D-1,25(OH)2D [A precursor (known specifically as vitamin D3 or cholecalciferol) is synthesized in a photochemical reaction in the skin], which activates the vitamin D receptors in the intestine to increase calcium absorption, in the parathyroid glands to decrease PTH secretion, and in bone to increase resorption.
This integrated hormonal response restores serum calcium.
With a rise in serum calcium, these actions are reversed, and the integrated hormonal response reduces serum calcium.
When the concentration of calcium rises, the parafollicular cells of the thyroid gland increase their secretion of calcitonin into the blood. At the same time, the parathyroid glands reduce their rate of parathyroid hormone secretion into the blood.
Calcitonin in the blood stimulates the skeleton to remove calcium from the blood plasma, and deposit it as the bone. The reduced levels of PTH inhibit removal of calcium from the skeleton. reduced parathyroid levels increase the loss of calcium in the urine and decrease phosphate excretion.
Increased phosphates in plasma bind calcium and remove calcium from blood.
Moreover decreased parathyroid levels inhibit the formation of calcitriol (1,25 dihydroxyvitamin D3) from cholecalciferol (vitamin D3) by the kidneys which affect to decrease the absorption of calcium from the intestine.
Low vitamin D3 level also causes osteoclasts to release less calcium ions into the blood plasma.
These feedback and regulatory mechanisms help to maintain total serum calcium within the narrow physiological range.
Disorders of Calcium
Hypocalcemia and hypercalcemia are terms used clinically to refer to abnormally low and high serum calcium concentrations. It should be noted that, because about one half of serum calcium is protein bound, abnormal serum calcium, as measured by total serum calcium, may occur secondary to disorders of serum proteins rather than as a consequence of changes in ionized calcium.
Hypocalcemia causes these channels to leak sodium into the nerve cells or axons, making them hyperactive and leading to spontaneous muscle spasms (tetany) and paraesthesiae.
hypercalcemia more calcium is bound to these sodium channels having a negative effect on them, causing lethargy, muscle weakness, anorexia, constipation, and labile emotions.
Hypercalcemia and hypocalcemia indicate serious disruption of calcium homeostasis but do not on their own reflect calcium balance. They can be classified by the main organ responsible for the disruption of calcium homeostasis.
In a healthy adult, approximately 30% of dietary ingested calcium is absorbed by the body in the small intestine.
Calcium absorption is controlled by 1,25 (OH) 2D by controlling a transport mechanism which accounts for the majority of absorption. About 8- 23% of overall calcium absorption is caused by passive diffusion.
Bioavailability of dietary calcium is lowered by calcium-binding agents such as cellulose, phosphate, and oxalate. Diseases of the small bowel like including celiac sprue and short bowel syndrome can result in severe calcium malabsorption.
Aluminum hydroxide binds dietary phosphate and may lead to increased calcium absorption. Increased levels of vitamin D3 cause hypercalcemia due to increased calcium absorption.
Sarcoidosis, hypervitaminosis D, excessive intake of cholesterol or its analogs are the usual causative factors.
In case of renal disease, normal amounts of dietary calcium may cause hypercalcemia because kidneys are unable to excrete excess calcium.
Low dietary calcium rarely causes hypocalcemia as the levels get compensated by homeostasis. But in states of low, or inappropriately low, serum 1,25(OH)2D [ chronic vitamin D deficiency, osteomalacia, and rickets or kidney disease] low absorption from the intestine may cause hypocalcemia.
Remodeling hypercalcemia results from increased bone resorption which may occur in primary hyperparathyroidism, and vitamin D poisoning and some malignancies.
Remodeling hypocalcemia when there is an increased net bone formation. For example in parathyroidectomy.
Bone can release to, and remove calcium from, driven by the serum calcium concentration itself.
Renal calcium excretion is regulated by tubular calcium reabsorption and filtered calcium load. Disruption of either or both of these mechanisms leads to abnormal calcium homeostasis.
Primary hyperparathyroidism, sodium depletion, thiazide medications, and mutations in the calcium-sensing receptors may cause increased tubular resorption of calcium leading to hypercalcemia
A decreased tubular calcium reabsorption as hypoparathyroidism, abnormalities in the PTH receptors and CaR may lead to hypocalcemia.
A decreased glomerular filtration rate in chronic kidney disease may lead to hypercalcemia.
Interaction of Calcium and Phosphate
Calcium and phosphate are closely linked. Calcium and phosphate (inorganic phosphorus) interact in several fundamental processes. Phosphorus was previously regarded as a passive companion of the calcium fluxes at gut and bone but newer studies have revealed that phosphate is regulated independently too. Two main hormones that affect phosphate regulation is a fibroblast growth factor and parathyroid hormone.
Calcium and phosphate together with other cells and proteins mineralize osteoid as it is deposited, but in a healthy person, a less understood mechanism prevents the calcium phosphate deposition in non-skeletal tissues.
In chronic renal disease, soft tissue calcification is common due to raised parathyroid levels.
An increase in serum phosphate stimulates FGF-23 secretion from the bone. This acts on the Na/Pi II co-transporters in proximal tubular cells of the kidney to decrease phosphate absorption.
At the same time, fibroblast growth factor 23 reduces renal secretion of 1,25 dihydroxy vitamin D 3 which decreases intestinal phosphate absorption.
Both these mechanisms work to reduce serum phosphate to normal levels.
A decrease in serum phosphate causes a reduction in serum FGF-23 which leads to restoration of serum phosphate.
Serum parathyroid levels also play a key role in phosphate homeostasis.
Increased serum parathyroid hormone acts on renal Na/Phosphorous ll co-transporters and decreases renal phosphate reabsorption and serum phosphate, whereas decreased PTH increases renal phosphate reabsorption and serum phosphate
Increased PTH stimulates 1,25(OH)2D secretion.
There is a complex coordination between calcium and phosphate homeostasis.
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