1. Summary of review: Calcium, phosphate and magnesium have
important intracellular and extracellular functions with their
metabolism often linked through common hormonal signals. A
predominant portion of total body calcium is unionised within bone
and serves an important structural function. Intracellular and
extracellular ionised calcium changes are often linked and have
important secretory and excitatory roles. The extracellular ionised
calcium is carefully regulated by parathyroid hormone and vitamin
D, whereas calcitonin is secreted largely in response to
hypercalcaemia.
2. Phosphorous is needed for bone structure although it also
has an important role in cell wall structure, energy storage as
ATP, oxygen transport and acid-base balance. Ionised calcium, in as
far as it controls PTH secretion, indirectly controls urinary
phosphate excretion. When plasma phosphate increases, tubular
reabsorption also increases up to a maximum, thereafter phosphate
is excreted. The minimum oral requirement for phosphate is about 20
mmol/day
3. Magnesium is a predominantly intracellular ion that acts as
a metallo-coenzyme in more than 300 phosphate transfer reactions
and thus has a critical role in the transfer, storage and
utilisation of energy within the body. Extracellular magnesium
concentrations are largely controlled by the kidneys with the renal
tubular maximum reabsorption controlling the plasma magnesium
concentration
4. INTRODUCTION: Calcium is the most abundant mineral in the
human body. The average adult body contains approximately 25 000
mmol (1 kg), of which 99% is bound in the skeleton. The total
calcium content of the extracellular fluid (ECF) is only 22.5 mmol,
of which about 9 mmol is in the plasma.
5. BONE Bone consists of osteoid, a collagenous organic matrix,
on which is deposited complex inorganic hydrated calcium salts
known as hydroxyapatites. These have the general formula:
Ca10(PO4)6(OH)2 Even when growth has ceased, bone remains
biologically active. Continuous turnover ('remodelling') occurs
with bone resorption (mediated by osteoclasts) being followed by
new bone formation (mediated by osteoblasts).
6. At any one time, about 5% of bone mass in adults is subject
to remodelling. This process is controlled and coordinated by
hormones, growth factors and cytokines. Bone formation requires
osteoid synthesis and adequate calcium and phosphate for the laying
down of hydroxyapatite.
7. Alkaline phosphatase, secreted by osteoblasts, is essential
to the process, probably acting by releasing phosphate from
pyrophosphate. Bone provides an important reservoir of calcium,
phosphate and, to a lesser extent, magnesium and sodium.
8. PLASMA CALCIUM In the plasma, calcium is present in three
forms: bound to protein (mainly albumin), complexed with citrate
and phosphate, and free ions. Only the latter form is
physiologically active and it is the concentration of ionized
calcium that is maintained by homoeostatic mechanisms.
9. In alkalosis, hydrogen ions dissociate from albumin, and
calcium binding to albumin increases. There is also an increase in
calcium complex formation. As a result, the concentration of
ionized calcium falls, and this may be sufficient to produce
clinical symptoms and signs of hypocalcaemia although total plasma
calcium concentration is unchanged. In an acute acidosis, the
reverse effect is observed, that is, the ionized calcium
concentration is increased.
10. The most frequently used methods for determining plasma
calcium concentration measure total calcium, although ionized
calcium can be measured using an ion-selective electrode.
Fortunately, measurements of total calcium are satisfactory for
most clinical purposes. Changes in plasma albumin concentration
will affect total calcium concentration independently of the
ionized calcium concentration, leading to possible
misinterpretation of results in both hypoproteinaemic and
hyperproteinaemic states.
11. Various formulae have been devised to indicate the total
calcium concentration to be expected if the albumin concentration
were normal. Although globulins bind calcium to a lesser extent
than albumin, the increase in - globulin in patients with myeloma
can also increase the total plasma calcium concentration.
12. CALCIUM-REGULATING HORMONES Calcium concentration in the
ECF is normally maintained within narrow limits by a control system
involving two hormones: parathyroid hormone (PTH) and calcitriol
(vit D) (1,25- dihydroxycholecalciferol). These hormones also
control the inorganic phosphate concentration of the ECF.
Calcitonin probably has only a minor role in calcium
homoeostasis.
13. Parathyroid hormone This hormone is a single-chain
polypeptide, comprising 84 amino acids; as with many peptide
hormones, it is synthesized as a larger precursor, pre-pro-PTH (115
amino acids). Prior to secretion, two amino acid sequences are
lost; the removal of a 25 amino acid chain produces pro-PTH, a
further six amino acids being removed to form PTH itself.
14. PTH is secreted by the parathyroid glands in response to a
fall in plasma (ionized) calcium concentration and secretion is
inhibited by hypercalcaemia. These effects are mediated by the
calcium- sensing receptor (CaSR). Calcitriol (see below) inhibits
PTH synthesis. PTH acts on bone and the kidneys, tending to
increase the plasma concentration of calcium and reduce that of
phosphate.
15. PTH mobilizes calcium from bone: this action is biphasic, a
rapid phase involving existing cells (probably osteocytes) and a
longer-term response dependent on the proliferation of osteoclasts.
In the kidneys, PTH increases the fraction of the filtered load
that is reabsorbed. However, because increased resorption of bone
increases the amount of calcium that is filtered, there is
hypercalciuria despite the increased reabsorption.
16. Also in the kidneys, PTH promotes phosphaturia by
decreasing the reabsorption of filtered phosphate and stimulates
the formation of calcitriol, the calcium-regulating hormone derived
from vitamin D.
17. Despite the importance of PTH in the control of phosphate
excretion, changes in phosphate concentration do not directly
affect secretion of the hormone. Mild hypomagnesaemia stimulates
PTH secretion, but more severe hypomagnesaemia reduces it, as the
secretion of PTH is magnesium dependent.
18. Actions of the Hormones Involved in Calcium Homeostasis
Hormone Effect on bones Effect on GI Effect on kidneys PTHCa++ ,
PO4 levels in blood Supports osteoclast resorption Indirect effects
via calcitriol from 1- hydroxylation Supports Ca++ resorption and
PO4 excretion, activates 1-hydroxylation Vitamin D Ca++ , PO4
levels in blood No direct effects Supports osteoblasts Ca++ and PO4
absorption No direct effects Calcitonin Ca++ , PO4 levels in blood
when hypercalcemia present Inhibits osteoclast resorption No direct
effects Promotes Ca++ and PO4 excretion
19. Calcitriol This hormone is derived from vitamin D by
successive hydroxylation in the liver (25- hydroxylation) and
kidneys (1- hydroxylation). In the gut, it stimulates absorption of
dietary calcium and phosphate; this process involves the synthesis
of a calcium-binding protein (calbindin D) in enterocytes.
20. Calcitriol is derived from a metabolite of cholesterol,
7-dehydro- cholesterol formed in the liver. Non-ezymatic breakage
of the B-ring by ultraviolet light exposure in the skin form
cholecalciferol (vitamin D3) which may also be obtained in the
diet, e.g., in vitamin D fortified milk. Liver hydroxylates chole-
calciferol on the sidechain to form 25- hydroxycholecalciferol
which is carried by the vitamin D carrier protein in serum to the
kidney. In the kidney the molecule can be hydroxylated once or
twice more to form the active hormone calcitriol or the inactive
metabolites 24,25-dihydroxycholecalciferol or 1, 24, 25-
trihydroxycholecalciferol. PTH promotes 1 hydroxylation &
activation, CT promotes 24 hydroxylation & inactivation.
21. Vitamin D 25(OH)D 1,25(OH)D 26 + cells throughout the body
7-dehydrocholesterol UVB photons
22. In bone, calcitriol promotes mineralization largely
indirectly, through its role in the maintenance of ECF calcium and
phosphate concentrations. The binding of calcitriol to osteoblasts
increases the production of alkaline phosphatase and of a
calcium-binding protein, osteocalcin, the exact function of which
is uncertain.
23. At high concentrations, calcitriol stimulates osteoclastic
bone resorption, which releases calcium and phosphate into the ECF.
In the kidneys, calcitriol inhibits its own synthesis. It may have
a small stimulatory effect on calcium reabsorption, acting
permissively with PTH.
24. Calcitonin This polypeptide hormone, produced by the
C-cells of the thyroid, is secreted when plasma calcium
concentration rises and also in response to certain gut hormones.
It can be shown experimentally to inhibit osteoclast activity, and
thus bone resorption, but its physiological role is uncertain.
Subjects who have had a total thyroidectomy do not develop a
clinical syndrome that can be ascribed to calcitonin
deficiency.
25. Plasma calcitonin concentration is elevated during
pregnancy and lactation. So, too, is calcitriol concentration, and
calcitonin may block the action of calcitriol on bone and permit
increased calcium uptake from the gut to take place to satisfy
increased requirements without loss of mineral from bone.
26. CALCIUM AND PHOSPHATE HOMOEOSTASIS Hypocalcaemia stimulates
the secretion of PTH and, through this, increases the production of
calcitriol. There is an increase in the uptake of both calcium and
phosphate from the gut and in their release from bone.
27. PTH is phosphaturic, so the excess phosphate is excreted
but the fractional reabsorption of calcium by the kidney is
increased, some of the mobilized calcium is retained and the plasma
calcium concentration tends to rise towards normal.
28. In hypophosphataemia, calcitriol secretion is increased but
PTH is not. Indeed, any tendency for calcitriol to increase the
plasma calcium concentration should inhibit PTH secretion. Calcium
and phosphate absorption from the gut are stimulated.
29. Calcitriol has a much smaller effect on renal calcium
reabsorption than PTH with the result that, in the absence of PTH,
the excess calcium absorbed from the gut is excreted in the urine.
The net outcome is the restoration of the phosphate concentration
towards normal, independently of that of calcium.
30. DISORDERS OF CALCIUM, PHOSPHATE AND MAGNESIUM METABOLISM
Hypercalcaemia Two conditions account for up to 90% of cases:
primary hyperparathyroidism and malignancy. Hypercalcaemia may be
discovered during the investigation of an illness of which it is
known to be a potential complication or during the investigation of
clinical features suggestive of hypercalcaemia. However,
hypercalcaemia is often clinically silent and discovered
incidentally when calcium is measured as part of a biochemical
profile.
31. Malignant disease This is a very common cause of
hypercalcaemia. Patients with hypercalcaemia and malignant disease
are usually symptomatic, owing to the malignancy, the
hypercalcaemia or both. With most solid tumours, it is due to the
secretion by the tumour of PTH-related peptide (PTHrP).
32. This is a peptide having some N-terminal amino acid
sequence homology with PTH. In patients with metastases in bone,
there is often no relationship between the extent of metastasis and
the severity of the hypercalcaemia, suggesting that humoral factors
may be involved. Other humoral factors that have been implicated
include transforming growth factors, prostaglandins and,
particularly in haematological malignancies, osteoclast- activating
cytokines.
33. Primary hyperparathyroidism The prevalence of this
condition is of the order of one case per 1000 persons. It is
usually due to a parathyroid adenoma, less often to diffuse
hyperplasia of the glands, and only rarely to parathyroid
carcinoma.
34. The definitive treatment for hyperparathyroidism is
surgery. Patients with mild (