The adult body contains around 1 – 1.2kg calcium (Ca2+), ninety nine per cent of which is stored in solid form within bone. Ionized Ca2+ present in the extracellular fluid and plasma (1 – 1.5g) is in equilibrium with the 1% or so of skeletal calcium which is readily exchangeable, with calcium entering the body through the GI tract (0.2 – 0.5g/day) and with calcium loss through the kidneys (0.15 -0.3g/day).
A typical adult daily diet will contain 2 – 5g calcium, only 10% of which is absorbed by the GI tract. Furthermore, plasma Ca2+ is readily filtered by the kidney with 98 -99% reabsorbed in the nephron. Thus, small changes in either calcium exchange with bone, calcium absorption in the GI tract or calcium reabsorption in the kidney can have very marked effect upon plasma and extracellular calcium levels. Unsurprisingly, these are sites of hormonal control.
Three hormones mediate calcium homeostasis: parathyroid hormone (PTH), 1,25-dihydroxycholecalciferal (1,25(OH)2 D3) and calcitonin. They also regulate phosphate (PO43-) balance and bone turnover.
Parathyroid hormone (PTH) is a polypeptide hormone secreted by the parathyroid glands. PTH release is triggered (within minutes) by falling plasma Ca2+ levels and it acts to increase plasma Ca2+ and so protect against hypocalcaemia. PTH acts on osteoblasts and on specific PTH receptors in the kidney to:
• stimulate osteoclast, and inhibit osteoblasts, releasing Ca2+ and PO43- from bone (bone resorption)
• increase Ca2+ reabsorption in the distal tubule and collecting duct of the kidney
• stimulate dihydroxyvitaminD3 production and release in the kidney. Dihydroxy-vitaminD3 in turn stimulates Ca2+ absorption by the gut.
• promotes renal phosphate (PO43-) loss through an action on Na-P transporter of the proximal tubule. Lower phosphate levels cause hydroxyapatite (the major crystalline form of calcium in bone) to re solubilise, increasing net bone resorption and releasing Ca2+ into the blood and ECF.
Rising plasma Ca2+ feeds back on the parathyroid glands to inhibit further PTH release (negative feedback loop). Hyperfunction of the parathyroid gland (primary hyperparathyroidism – most often due to a parathyroid adenoma) is a common cause of hypercalcaemia.
DihydroxyvitaminD3 (also known as 1,25(OH)2 D3, cholecalciferol or calcitriol) is a metabolite of vitamin D. Vitamin D compounds are supplied in the diet or by the action of sunlight on cholesterol precursors in the skin. Hydroxylation of one of these, vitamin D3, in the liver and kidneys produces the active hormone dihydroxyvitaminD3 1,25(OH)2D3. DihydroxyvitaminD3 production is stimulated by low plasma Ca2+, low phosphate (PO43-) and PTH action on vitamin D3 hydroxylation in the kidney.The major physiological role of dihydroxyvitaminD3 appears to be the maintenance of whole body Ca2+ through increasing absorbtion of dietary Ca2+ from the intestine. Severe vitamin D deficiency (and consequent low levels of dihydroxyvitaminD3) leads to demineralised or soft bones – rickets in children and osteomalacia in adults.
Calcitonin is a polypeptide hormone produced by parafollicular cells (C-cells) of the thyroid gland. It is released in response to raised plasma Ca2+ levels and acts to lower plasma calcium, therefore opposing the action of PTH. Calcitonin stimulates osteoblast and inhibits osteoclast activity, thereby reducing bone turnover and promoting calcium uptake from plasma and ECF into bone. It also inhibits renal Ca2+ and PO43- reabsorption in the kidney. Importantly, during pregnancy and lactation, calcitonin protects against maternal bone loss from high calcium demand by the baby.
These mechanisms tightly regulate plasma calcium [Ca2+] between 2.15 and 2.65mmol/L. Roughly half (50%) plasma Ca2+ is bound to plasma proteins (albumin mostly) and half freely diffusible as Ca2+ ions. Total calcium concentration (Ca2+Total) therefore varies with albumin level and a corrected calcium level (Ca2+Corrected) can be calculated where plasma albumin concentration differs significantly from normal (40g/dL). Only the unbound form, free Ca2+, is physiologically active.
Figure 1. Calcium Homeostasis.