section 37.1
Calcium and Phosphorus
m ost proPTH is rapidly degraded at a rate that parallels
changes in extracellular Ca2+ concentration.
Chronic hypocalcem ia leads to hypertrophy and hyper-
plasia o f the parathyroid glands, w hereas chronic hyper-
calcem ia has the opposite effect. D N A synthesis is prob-
ably involved.
A t normal levels o f calcium , a decrease in M g2+
stim ulates PTH secretion, w hile an increase in M g2+
inhibits it. A lthough the effects o f M g2+ and Ca2+ are
qualitatively sim ilar, Ca2+ is tw o to four tim es as potent
as M g2+. In hum ans, PTH secretion is suppressed by
hyperm agnesem ia
(three tim es
norm al),
w hen accom panied by hypocalcem ia. A lthough m oderate
hypom agnesem ia
stim ulates
extrem ely
low levels o f M g2+
severely decrease the secretion
and peripheral effectiveness o f PTH, p ossib ly because
o f the need for M g2+ for adenylate cyclase activity.
Epinephrine, other ^-adrenergic agents, and exogenou s
cA M P stim ulate PTH secretion, w hereas 1,24 (O H )2D
decreases PTH gen e transcription and thus its synthesis
and secretion. Target tissues for PTH are bone and kidney.
PTH affects intestinal calcium absorption on ly indirectly,
by regulating l,2 5 -(O H )2D . T he action o f PTH on target
cells is m ediated by its binding to a distinct fam ily o f
plasm a m em brane G -protein-coupled receptors, follow ed
by stim ulation o f adenylate cyclase and cA M P production.
Parathyroid horm one-related protein also binds to the
sam e receptor in initiating its biological actions (discussed
In bone,
PTH prom otes resorption and new -bone
form ation. B on e dissolution predom inates at high con -
centrations o f PTH , w hile form ation is m ore important
at p hysiological levels. PTH also stim ulates calcium re-
lease independently o f resorption and m ore rapidly than
it stim ulates resorption. This pathway is probably m ost
important in short-term regulation o f the serum calcium
level. C alcium released in this w ay m ay com e from a pool
o f soluble calcium in the extracellular fluid o f bone.
PTH prom otes bone resorption by increasing the num -
ber o f osteoclasts. PTH stim ulates osteoclastic co lla g e-
nase activity and release o f lysosom al hydrolases. T hese
enzym es degrade the organic matrix o f bone and increase
urinary excretion o f hydroxyproline and hydroxylysine.
D ecrease in local pH from accum ulation o f organic acids
m ay aid in this process. A lthough PTH causes cA M P ac-
cum ulation in the skeleton and cA M P analogues increase
bone resorption, PTH analogues that b lock the increase
in cA M P have no effect
in vitro
on stim ulation o f bone
resorption by PTH.
o f
2 5 -(O H )D -la -
Proxim ally
hibits reabsorption o f calcium , phosphate, sodium , and
bicarbonate. T he effect on sodium and bicarbonate is
probably not p h ysiologically important, since regulation
o f their excretion is accom plished in the distal tubule
(Chapter 39), w here PTH does not affect their concentra-
tions. The proxim al effects require higher concentrations
o f PTH than the distal effects.
Norm ally, 65 -8 0 % o f filtered calcium and 85-90% o f
filtered phosphate are reabsorbed, m ainly in the proxi-
m al tubule. The daily loss o f 7 0 0 -8 0 0 m g o f phosphate
is balanced by dietary intake. Fine-tuning o f calcium ex -
cretion is accom plished by PTH in the distal convoluted
tubules and collectin g ducts. Phosphate excretion is reg-
ulated by PTH in the proxim al tubules. Elevation o f the
PTH level increases reabsorption o f calcium and decreases
reabsorption o f phosphate from the tubules. This phos-
phaturic action op poses the phosphate-sparing action o f
1.25- (O H )
U rine concentrations o f cA M P are norm ally 100 tim es
higher than those in plasm a or cytoplasm . Urinary cA M P is
form ed by action o f PTH on the renal tubules. In hypocal-
cem ia due to pseudohypoparathyroidism , reabsorption o f
Ca2+ from the collectin g ducts is im paired because the
cells do not respond to PTH. Serum levels o f PTH are
high, but the urine contains very little cAM P. The defect
m ay be in the receptors for PTH or distal to the recep-
tor. PTH m ay also affect tubular reabsorption by cA M P -
independent m echanism s.
Thus, a com plex relationship exists am ong serum Ca2+
and phosphate, PTH, and vitam in D and its m etabolites.
R elease o f PTH in response to low serum Ca2+ directly
m obilizes calcium from bone and increases synthesis o f
1.2 5 - (O H )
D , w hich in turn m obilizes skeletal Ca2+ and
causes increased intestinal calcium absorption. T hese e f-
fects raise the serum Ca2+ level sufficiently to reduce PTH
secretion. T he effect o f PTH on the kidneys occurs w ithin
m inutes, w hereas the effects o f PTH on bone and (indi-
rectly) on intestine take hours and days, respectively. A n
increase in serum phosphate acts in a w ay qualitatively
sim ilar to that o f h ypocalcem ia to release PTH , increase
excretion o f phosphate in the proxim al tubules, and d e-
crease intestinal phosphate absorption. T hese events are
m ediated predom inantly by the decrease in serum calcium
that accom panies a rise in phosphate concentration. In ad-
dition, phosphate m ay inhibit 2 5 -(O H )D -la -h y d ro x y la se.
Primary hyperparathyroidism
results from hyperpla-
sia, adenom a, or carcinom a o f the parathyroid glands and
from ectopic production o f the horm one by squam ous cell
carcinom a o f the lung or by adenocarcinom a o f the kidney.
In about 10% o f hyperparathyroidism , hyperplasia or tu-
m ors o f the parathyroid glands occur due to fam ilial disor-
ders know n as m ultiple endocrine neoplasia (M E N ). M E N
syndrom es con sist o f three subtypes (I, IIA, IIB) and are
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