Porth's Essentials of Pathophysiology, 4e - page 1086

C h a p t e r 4 2 Structure and Function of the Skeletal System 1069
determines skeletal mass at any given time. The sequence
of bone resorption and bone formation begins with
osteoclastic resorption of existing bone, during which
the organic (protein matrix) and the inorganic (mineral)
components are removed. The sequence proceeds to the
formation of new bone by osteoblasts. In the adult, the
length of one sequence (i.e., bone resorption and forma-
tion) is approximately 4 months. Ideally, the replaced
bone should equal the absorbed bone. If it does not,
there is a net loss of bone. In the elderly, for example,
bone resorption and formation no longer are perfectly
coupled, and bone mass is lost.
Recently, significant progress has been made in under-
standing the phenomenon of bone remodeling as it
relates to the coupling of bone resorption with bone for-
mation. The pivotal paracrine pathway linking these two
processes consists of three factors: RANKL (for receptor
activator of nuclear factor-κB legend); its receptor, RANK;
and a soluble inhibitor receptor for RANKL called osteo-
protegerin (OPG). RANKL is expressed by osteoblasts
and their immature precursors and is necessary for osteo-
clast differentiation and function. RANKL activates its
receptor, RANK, which is expressed on osteoclasts and
their precursors, thus promoting osteoclast differentia-
tion and activation and prolonging osteoclast survival by
suppressing apoptosis. The fact that RANKL is expressed
on osteoblasts indicates that bone resorption and bone
formation are linked through RANKL. The effects of
RANKL are blocked by OPG, a soluble receptor protein,
which acts as a decoy receptor that binds RANKL and
prevents it from binding with RANK on osteoclasts.
It is now believed that dysregulation of the RANKL/
RANK/OPG pathway plays a prominent role in the
pathogenesis of bone diseases such as osteoporosis (low
bone density). For example, it has been shown that post-
menopausal women express higher levels of RANKL on
their marrow stromal cells and lymphocytes than pre-
menopausal women or postmenopausal women taking
estrogen. It has also been shown that estrogens and the
selective estrogen receptor modulator, raloxifene, stim-
ulate OPG production in osteoblasts. Glucocorticoid
exposure, which can contribute to steroid osteoporo-
sis, enhances RANKL expression and suppresses OPG
levels, thus elevating the RANKL-to-OPG ratio. There is
also evidence linking the pathogenesis of inflammatory
conditions such as rheumatoid arthritis to dysregulation
of the RANKL/OPG system.
Hormonal Control of Bone Formation
and Metabolism
The process of bone formation and mineral metabolism
is complex. It involves the interplay among the actions
of parathyroid hormone (PTH), calcitonin, and vitamin
D (Table 42-2). Other hormones, such as corticosteroid
hormone, growth hormone, thyroid hormone, and the
sex hormones, also influence bone formation directly or
indirectly.
Parathyroid Hormone. Parathyroid hormone, which
is produced by the parathyroid glands embedded in
the thyroid gland, is one of the important regulators of
calcium and phosphate levels in the blood. Parathyroid
hormone prevents serum calcium levels from falling
below and serum phosphate levels from rising above
normal physiologic concentrations (see Chapter 8). The
secretion of PTH is regulated through negative feed-
back related to serum levels of ionized calcium, with
decreased levels stimulating PTH release and increased
levels inhibiting its release.
Parathyroid hormone maintains serum calcium levels
by promoting bone resorption, conserving calcium by
the kidney, enhancing intestinal absorption of calcium
through activation of vitamin D, and reducing serum
phosphate levels (Fig. 42-5). Parathyroid hormone also
increases the movement of calcium and phosphate from
bone into the extracellular fluid. In the kidney, PTH stim-
ulates tubular reabsorption of calcium while reducing the
reabsorption of phosphate. The latter effect ensures that
the increased release of phosphate frombone during mobi-
lization of calcium does not produce an elevation in serum
phosphate levels. This is important because an increase in
calcium and phosphate levels could lead to crystallization
in soft tissues. Parathyroid hormone also stimulates the
activation of vitamin D by the kidney, thereby increasing
the absorption of calcium from the intestine.
TABLE 42-2 Actions of Parathyroid Hormone, Calcitonin, andVitamin D
Actions Parathyroid Hormone Calcitonin Vitamin D
Intestinal absorption of calcium Increases indirectly through
increased activation of
vitamin D
Probably has no effect Increases
Intestinal absorption of phosphate Increases Probably has no effect Increases
Renal excretion of calcium Decreases Minor effect Probably increases, but less
effect than PTH
Renal excretion of phosphate Increases Minor effect Increases
Bone resorption Increases Decreases 1,25-(OH)2D3 increases
Bone formation Decreases Uncertain 24,25-(OH)2D3 increases
Serum calcium levels Produces a prompt
increase
Decreases with
pharmacologic doses
No effect
Serum phosphate levels Prevents an increase Decreases with
pharmacologic doses
No effect
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