Disorders of calcium, phosphate and magnesium

metabolism

Calcium is the most abundant mineral in the body, there being

about 25 mol (1 kg) in a 70 kg man. Approximately 99% of
the body's calcium is present in the bone, mainly as the
mineral hydroxyapatite, where it is combined with phosphate.
About 85% of the body's phosphate content is in the bone.
Calcium' is used as a composite term that embraces ionised
calcium, protein-bound calcium and complexed calcium,
whereas Ca2+ means that only calcium ions are being
considered. The total concentration of calcium in serum or
urine is shown as serum or urine [calcium], whereas plasma
[Ca2+] refers specifically (and solely) to the concentration of
ionised calcium.

Calcium homeostasis

Calcium balance

In adults, calcium intake and output are normally in balance

(Figure 1). External balance is largely achieved through the
body normally matching net absorption over 24 h closely with
the corresponding 24-h urinary excretion; this varies with the
diet. In infancy and childhood, there is normally a positive
balance, especially at times of active skeletal growth. In older
age, calcium output may exceed input, and a state of negative
balance then exists; this negative external balance is
particularly marked in women after menopause, and is
important in the development of post-menopausal
osteoporosis. In women, the mother loses calcium to the fetus
during pregnancy, and by lactation.

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Biological function of calcium

1. Calcium is a major mechanical constituent of the bone.

Bone by itself is a specialised mineralised connective
tissue containing cellular elements (bone- forming
osteoblasts and bone-resorbing osteoclasts), organic
matrix (type I collagen, proteoglycan, etc.) and the
calcium-containing mineral hydroxyapatite.
2. Calcium in the bone also acts as a reservoir that helps
to stabilise ECF [Ca2+]. Maintenance of extracellular
[Ca2+] within narrow limits is necessary for normal
excitability of nerve and muscle. The ion is also
required in the activation of the clotting and
complement cascades.
3. Cells possess a number of transport mechanisms for
Ca2+ that allow maintenance of this large gradient
across the cell membrane. An increase in cytosolic
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 [Ca2+] serves as a signal for several cell processes,
which include cell shape change, cell motility,
metabolic changes, secretory activity and cell division.

Metabolism

Calcium is present in plasma in three forms in equilibrium

with one another.

1. Ionised calcium, Ca2+ (50–65%)

2. Calcium bound to plasma proteins – mainly albumin
(30–45%)
3. Calcium complexed with citrate (5–10 %)

Plasma [Ca2+] is the physiologically important component,

and is closely regulated in humans by PTH and 1:25-
dihydroxy- cholecalciferol(DHCC): both act to increase
plasma [Ca2+] and hence plasma [calcium]. The body's
responses to a fall in plasma [Ca2+], in terms of changes in
PTH and 1:25-DHCC production, are shown in Figure.2 .

Figure .2 Calcium homeostasis in man showing the main

hormonal responses to a fall in plasma [Ca2+], and indicating
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the places where the negative feedback mechanism operates if
plasma [Ca2+] becomes high. The effect of PTH on the renal
tubules, causing increased reabsorption of calcium.

Parathyroid hormone (PTH)

PTH is the principal acute regulator of plasma [Ca2+].

Plasma PTH levels exhibit a diurnal rhythm, being highest in
the early hours of the morning and lowest at about 9 am. The
active hormone is secreted in response to a fall in plasma
[Ca2+], and its actions are directed to increase plasma
[Ca2+]. An increase in plasma [Ca2+] suppresses PTH
secretion.

Actions of PTH :

1. In bone, PTH stimulates bone resorption by osteoclasts,

with a requirement for osteoblasts to mediate this
effect. Biochemical measures of both increased
osteoblast activity (e.g. increased serum ALP activity)
and increased osteoclast activity (e.g. raised urinary
hydroxyproline and deoxypyridinoline excretion) may
be evident.
2. In the kidney, PTH increases the distal tubular
reabsorption of calcium. It also reduces proximal
tubular phosphate reabsorption and promotes activity
of the 1α-hydroxylation of calcidiol. Formation of
1:25-DHCC indirectly increases the absorption of
calcium from the small intestine.

1:25-Dihydroxycholecalciferol (1:25-DHCC, or calcitriol)

Most vitamin D3 (cholecalciferol) is synthesised by the action

of ultraviolet light on the vitamin D precursor 7-
dehydrocholesterol in the skin. Vitamin D3 is also present
naturally in food (a rich source is fish oils), while vitamin D2
(ergosterol) is added to margarine. Endogenous synthesis of

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vitamin D3 is important. Vitamin D deficiency can develop if
exposure to sunlight is inadequate, or because of inadequate
dietary intake, but is usually a result of the combined effects
of these two factors. In the body, vitamin D3 and vitamin D2
undergo two hydroxylation steps before attaining full
physiological activity(Figure 3):
1. 25-HydroxyIation This occurs in the liver, with the
production of 25-hydroxycholecalciferol (25-HCC, or
calcidiol). Other inactive metabolites are formed, but
are excreted in the bile. The main form of vitamin D
circulating in the plasma is 25-HCC, bound to a
specific transport protein; it is carried to the kidney for
further metabolism. Plasma [25-HCC] shows marked
seasonal variation, with levels highest in summer.
2. 1α-Hydroxylation of 25-HCC This takes place in the
kidney, with the production of 1:25-DHCC,
biologically the most active naturally occurring
derivative of vitamin D. The kidney also contains other
hydroxylases, such as 24-hydroxylase, which converts
25-HCC to 24:25-DHCC. Renal 1α-hydroxylation is
increased by low plasma [phosphate], high [PTH] and
where there is a tendency to hypocalcaemia.
The principal action of 1:25-DHCC is to induce synthesis of a
Ca2+-binding protein in the intestinal epithelial cell necessary
for the absorption of calcium from the small intestine.
Deficiency of 1:25-DHCC leads to defective bone
mineralisation. Maintenance of both ECF [Ca2+] and ECF
[phosphate] by 1:25-DHCC may be a key factor in normal
mineralisation.

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Figure 3 : The formation of 1:25-DHCC, the most active form of
vitamin D3, from pro- vitamin D3 (normally the main source of the
vitamin in man) and from dietary vitamin D3. Vitamin D2 (ergosterol)
undergoes similar hydroxylations. By the action of ultraviolet (UV)
light, pro-vitamin D3 is converted in the dermis into previtaminD3; pre-
vitamin D3 then rearranges spontaneously to give vitamin D3.

Calcitonin

Its secreted from c-cell of thyroid gland. Although calcitonin

can decrease plasma [Ca2+] by reducing osteoclast activity
and decreasing renal reabsorption of calcium and phosphate,
its actions are transient, and chronic excess or deficiency is
not associated with disordered calcium or bone metabolism.

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