144 Introduction to Human Nutrition
● Calcitriol acts to reduce its own synthesis and
increase formation of 24-hydroxycalcidiol, by regu-
lating the expression of the genes for the two
hydroxylases.
● Parathyroid hormone is secreted in response to a
fall in plasma calcium. In the kidney it acts to
increase the activity of calcidiol 1-hydroxylase and
decrease that of 24-hydroxylase. In turn, both cal-
citriol and high concentrations of calcium repress
the synthesis of parathyroid hormone; calcium also
inhibits the secretion of the hormone from the
parathyroid gland.
● Calcium exerts its main effect on the synthesis
and secretion of parathyroid hormone. However,
calcium ions also have a direct effect on the kidney,
reducing the activity of calcidiol 1-hydroxylase.
● Phosphate also affects calcidiol metabolism;
throughout the day there is an inverse fl uctuation
of plasma phosphate and calcitriol, and feeding
people on a low-phosphate diet results in increased
circulating concentrations of calcitriol.
Metabolic functions of vitamin D
The principal function of vitamin D is to maintain
the plasma concentration of calcium; calcitriol
achieves this in three ways:
● increased intestinal absorption of calcium
● reduced excretion of calcium by stimulating resorp-
tion in the distal renal tubules (due to increased
calbindin D synthesis)
● mobilization of bone mineral.
There is a growing body of evidence that low vitamin
D status (but not such a degree of defi ciency as to
disturb calcium homeostasis) is associated with
impaired glucose tolerance, insulin resistance and
non-insulin dependent diabetes mellitus, as well as
obesity and the low grade chronic infl ammation asso-
ciated with (especially abdominal) obesity. There is
also evidence poor vitamin D status is a factor in the
etiology of some cancers. Calcitriol has a variety of
permissive or modulatory effects; it is a necessary, but
not suffi cient, factor, in:
● synthesis and secretion of insulin, parathyroid, and
thyroid hormones;
● inhibition of production of interleukin by activated
T-lymphocytes and of immunoglobulin by acti-
vated B-lymphocytes;
● differentiation of monocyte precursor cells;
● modulation of cell differentiation, proliferation and
apoptosis.
In most of its actions, the role of calcitriol seems to
be in the induction or maintenance of synthesis of
calcium binding proteins, and the physiological effects
are secondary to changes in intracellular calcium
concentrations.
Calcitriol acts like a steroid hormone, binding to a
nuclear receptor protein, commonly as a heterodimer
with the RXR (vitamin A) receptor, then binding to
hormone response elements on DNA and modifying
the expression of one or more genes.
The best-studied actions of vitamin D are in the
intestinal mucosa, where the intracellular calcium
binding protein induced by vitamin D is essential for
the absorption of calcium from the diet. Vitamin D
also acts to increase the transport of calcium across
the mucosal membrane by recruiting calcium trans-
port proteins to the cell surface.
Calcitriol also raises plasma calcium by stimulating
the mobilization of calcium from bone. It achieves
this by activating osteoclast cells. However, it acts later
to stimulate the laying down of new bone to replace
the loss, by stimulating the differentiation and recruit-
ment of osteoblasts.Vitamin D defi ciency:
rickets and osteomalacia
Historically, rickets is a disease of toddlers, especially
in northern industrial cities. Their bones are under-
mineralized as a result of poor absorption of calcium
in the absence of adequate amounts of calcitriol.
When the child begins to walk, the long bones of the
legs are deformed, leading to bow-legs or knock knees.
More seriously, rickets can also lead to collapse of the
ribcage and deformities of the bones of the pelvis.
Similar problems may also occur in adolescents who
are defi cient in vitamin D during the adolescent
growth spurt, when there is again a high demand for
calcium for new bone formation.
Osteomalacia is the adult equivalent of rickets. It
results from the demineralization of bone, rather than
the failure to mineralize it in the fi rst place, as is the
case with rickets. Women who have little exposure to
sunlight are especially at risk from osteomalacia after
several pregnancies, because of the strain that preg-
nancy places on their marginal reserve of calcium.