Regulation of Metabolism 693Effects of Other Hormones
People with hyperthyroidism are more prone to osteoporo-
sis. Since both osteoblasts and osteocytes have receptors for
T 3 (triiodothyronine, derived from thyroxine—see chapter 11,
figs. 11.6 and 11.7), the thyroid hormones would seem to be
implicated. However, the possible role of thyroid hormones in
bone physiology is poorly understood.
Leptin is a hormone discussed previously that is secreted by
adipocytes and acts on the hypothalamus to reduce hunger and
(through stimulation of sympathoadrenal activity) increase meta-
bolic rate. Leptin also indirectly decreases bone mass. It does this
by acting on the brain to stimulate sympathetic axons innervat-
ing osteoblasts. The binding of norepinephrine to b 2 -adrenergic
receptors on the osteoblasts stimulates these cells to secrete
RANK ligand (RANKL), which binds to RANK receptors to
stimulate the development of osteoclasts.
Insulin inhibits osteoblasts from producing osteoprotegerin,
a molecule that binds to RANKL and thereby blocks it from
stimulating osteoclast development. By this means, insulin acts to
increase the number of osteoclasts. The acidic environment cre-
ated by active osteoclasts then activates a bone hormone known
as osteocalcin. Release of active osteocalcin into the blood stimu-
lates the beta cells of the islets to secrete insulin. Thus, insulin
promotes the secretion of active osteocalcin, which then promotes
the secretion of insulin. This represents a previously unknown
positive feedback mechanism and ties together the regulation of
energy metabolism and bone discussed in this chapter. This mech-
anism is opposed by leptin, which indirectly reduces osteocalcin
activity and thereby contributes to blood glucose homeostasis.1,25-Dihydroxyvitamin D 3
The duodenum and jejunum of the small intestine can absorb
Ca^2 1 present in food by active transport across the intestinal epi-
thelial cells. Active transport is needed when the dietary Ca^2 1 is
low and a concentration gradient prevents passive transport. This
active, transcellular transport is stimulated by a form of vitamin
D known as 1,25-dihydroxyvitamin D 3.
The production of 1,25-dihydroxyvitamin D 3 begins in
the skin, where vitamin D 3 is produced from its precursor
(7-dehydrocholesterol) under the influence of the ultraviolet B in
sunlight. In equatorial regions of the globe, exposure to sunlight
can allow sufficient cutaneous production of vitamin D 3. In more
northerly or southerly latitudes, however, exposure to the winter
sun may not allow sufficient production of vitamin D 3. When
the skin does not make sufficient amounts of vitamin D 3 , this
compound must be ingested in the diet—that is why it is called
a vitamin. Production of vitamin D in the skin provides most
of a person’s vitamin D; food sources of vitamin D—including
fortified milk, eggs, and fish—provide only an average of 10%
to 20% (in the absence of vitamin D supplementation). Whether
this compound is secreted into the blood from the skin or enters
the blood after being absorbed from the intestine, vitamin D 3
functions as a prehormone; in order to be biologically active, it
must be chemically changed (chapter 11, section 11.1).
An enzyme in the liver adds a hydroxyl group (OH) to carbon
number 25, which converts vitamin D 3 into 25-hydroxyvitamin D 3.
In order to be active, however, another hydroxyl group must be
added to carbon number 1. Hydroxylation of the first carbon is
accomplished by an enzyme in the kidneys, which converts the
molecule to 1,25-dihydroxyvitamin D 3 ( fig. 19.21 ). The activity
of this enzyme in the kidneys is stimulated by parathyroid hor-
mone (see fig. 19.19 ). Increased secretion of PTH, stimulated by
low blood Ca^2 1 , is thus accompanied by the increased production
of 1,25-dihydroxyvitamin D 3.
The hormone 1,25-dihydroxyvitamin D 3 helps raise the
plasma concentrations of calcium and phosphate through sev-
eral mechanisms. It enters intestinal epithelial cells (primar-
ily in the duodenum) to stimulate the genetic transcription
of proteins needed for the active transport of Ca^2 1 across the
cell’s apical and basal surfaces to the extracellular fluid. This
action is necessary for the intestinal absorption of Ca^2 1 when
the plasma concentration of Ca^2 1 is low, which are the condi-
tions that promote the secretion of PTH and the formation of
1,25-dihydroxyvitamin D 3.CLINICAL APPLICATION
Osteoporosis, the most common bone disorder, is charac-
terized by parallel losses of mineral and organic matrix that
reduce bone mass and density ( fig. 19.20 ) and increase the
risk of fractures. It is about 10 times more common in women
after menopause than in men at comparable ages, which
suggests that osteoporosis is promoted by the fall in estro-
gen secretion at menopause. Withdrawal of estrogen may
increase the activity of osteoclasts and favor bone resorp-
tion over deposition. In this regard, estrogen replacement
therapy is effective in postmenopausal women who can
tolerate it. Decreased estrogen in men (formed in bone from
aromatization of testosterone) over age 55 is believed to also
contribute to the osteoporosis that can occur in men, and
testosterone replacement (along with other drugs) is some-
times used to help alleviate the bone loss.
The bisphosphonates ( Fosamax, Boniva, and others)
are the most commonly used drugs for treating osteopo-
rosis. They bind to the hydroxyapatite minerals and disrupt
the ability of the osteoclast’s ruffled border to bind to bone;
they also promote apoptosis of the osteoclasts and through
both actions reduce bone resorption. Roloxifene ( Evista ), a
selective estrogen receptor modulator (a SERM; chapter 11,
section 11.2), may be used to provide estrogenic support of
bone while minimizing some of the effects of estrogen on
other organs. Teriparatide ( Forteo ) is a parathyroid hor-
mone derivative that may be injected to increase bone mass.
Another possible hormone therapy is the use of calcitonin
(derived from salmon) as an injection or nasal spray. Calcium
supplementation of 1,200 to 1,500 mg/day, taken in doses of
600 mg or less to allow sufficient intestinal absorption, is rec-
ommended, along with vitamin D 3 (800 to 1,000 IU/day) to
lower the risks of osteoporosis.