The drugs that are used clinically to modulate bone homeostasis
can be divided into endogenous molecules and exogenous substances
The two hormones that serve as the principal regulators of calcium
and phosphate homeostasis are parathyroid
hormone (PTH), a protein, and biologically active metabolites
of the steroid vitamin D (Figure 25–2).
Other hormones such as calcitonin, prolactin, growth hormone, insulin,
thyroid hormone, glucocorticoids, and gonadal steroids serve secondary
roles in calcium and phosphate homeostasis. Several of these hormones,
such as calcitonin, glucocorticoids, and estrogens, have efficacy
in the treatment of bone mineral disorders. In addition, calcium,
phosphate, and other ions such as sodium alter calcium and phosphate
Mechanisms that contribute to bone mineral homeostasis.
Calcium (Ca) and phosphorus (P) concentrations in the serum are
controlled principally by two hormones: 1,25-dihydroxyvitamin D
(calcitriol; D) and parathyroid hormone
(PTH). Serum concentrations are regulated
by the action of D and PTH on absorption from the gut and bone and
on excretion in the urine. Both hormones remove calcium and phosphorus
from bone, increasing serum ion concentrations (+);
vitamin D also increases absorption from the gut (+).
Vitamin D decreases (–) urinary excretion of both
calcium and phosphorus, while PTH reduces (–) calcium
but increases (+) phosphorus excretion.
Calcitonin (CT) is a less critical
hormone for calcium homeostasis, but in pharmacologic concentrations,
CT can reduce (–) serum calcium and phosphorus
by inhibiting bone resorption and stimulating their renal excretion
(+). Feedback effects are not shown.
Vitamin D, a derivative of 7-dehydrocholesterol, is formed in
the skin under the influence of ultraviolet light. Vitamin D is
also found in some foods and is a nutritional additive in milk and
in calcium supplements. Active metabolites of vitamin D are formed
in the liver (25-hydroxyvitamin D, or calcifediol)
and the kidney (1,25-dihydroxyvitamin D [1,25[OH]2D3],
or calcitriol, plus other metabolites).
Because it is a fat-soluble vitamin, excess vitamin D is stored
in adipose tissue. The metabolites of vitamin D differ in the number
of hydroxyl groups attached to the steroid ring (Table 25–1).
The actions of these metabolites include increased intestinal calcium
and phosphorus absorption, decreased renal excretion of minerals,
and a net increase in blood levels of both calcium and phosphorus
(Figure 25–2, Table 25–2). These actions are mediated
by activation of one or possibly a family of nuclear receptors that
regulate gene expression. Of the vitamin D metabolites, 1,25[OH]2D
is the most potent in stimulating intestinal calcium and phosphate
absorption and bone resorption. In
contrast, bone formation can be increased
by the administration of a different metabolite, 24,25-dihydroxyvitamin
D (secalcifediol, 24,25(OH)2D3
Vitamin D supplements and synthetic derivatives are used in the
treatment of deficiency states, such as nephrotic syndrome and
nutritional rickets. They are also used, in combination with calcium
supplementation and other drugs, in the prevention and treatment
of osteoporosis in older women and men. Moreover, a number of calcitriol
analogs are being synthesized in an effort to examine their clinical
usefulness in a variety of nonclassic conditions. For example, calcipotriene (calcipotriol) is currently
used to treat psoriasis, a hyperproliferative skin disorder. Doxercalciferol and paricalcitol have recently been approved
for treating secondary hyperparathyroidism in patients with renal failure.
Table 25–1. Vitamin
D and Its Clinically Available Metabolites and Analogs
Table 25–2. Actions
of Parathyroid Hormone and Vitamin D on Gut, Bone, and Kidney ||Download (.pdf)
Table 25–2. Actions
of Parathyroid Hormone and Vitamin D on Gut, Bone, and Kidney
|Intestine||Increased calcium and phosphate absorption by 1,25(OH)2D||Increased calcium and phosphate absorption (by increased 1,25 [OH]2D
|Kidney||Calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D||Decreased calcium excretion, increased phosphate excretion|
|Bone||Increased calcium and phosphate resorption by 1,25(OH)2D;
bone formation may be increased by 24,25(OH)2D||Calcium and phosphate resorption increased by high doses. Low
intermittent doses increase bone formation|
|Net effect on serum levels||Serum calcium and phosphate both increased||Serum calcium increased, serum phosphate decreased|
By regulating calcium and phosphate flux across cellular membranes
in bone and kidney, PTH increases serum calcium while decreasing
serum phosphate (Figure 25–2, Table 25–2). By
an indirect mechanism, PTH increases the activity and number of
osteoclasts, cells responsible for bone resorption. PTH activates
G protein–coupled receptors on bone–forming osteoblasts, inducing
a membrane-bound protein called RANK ligand. RANK ligand increases
both the number and activity of osteoclasts. Thus, bone remodeling
is actually initiated by osteoclastic bone resorption and followed
by osteoblastic bone formation. Although PTH enhances both bone resorption
and bone formation, the net effect of excess PTH is increased bone
resorption. However, when administered in low, intermittent doses,
PTH increases bone formation without stimulating bone resorption.
Based on this effect, recombinant PTH 1-34 (teriparatide)
has been approved by the United States Food and Drug Administration
(FDA) for the treatment of osteoporosis in postmenopausal women.
In the kidney, PTH increases calcium and magnesium resorption while
reducing the resorption of phosphate, amino acids, bicarbonate,
sodium, chloride, and sulfate. Another important action of PTH in
the kidney is its stimulation of calcitriol production.
of PTH and Vitamin D Metabolites
A summary of the principal actions of PTH and vitamin D on intestine,
kidney, and bone is presented in Table 25–2. The net effect
of PTH is to raise serum calcium and reduce serum phosphate; the
net effect of vitamin D is to raise serum levels of both. Regulation
of calcium and phosphate homeostasis is achieved through a variety
of feedback loops. In the parathyroid gland, specialized G protein–coupled
receptors sense extracellular calcium concentration and couple this with
intracellular calcium concentration. For example, when extracellular
calcium falls, intracellular calcium falls in parallel and parathyroid
cells secrete more PTH. Conversely, a rise in intracellular calcium
concentration in parathyroid cells inhibits PTH secretion. Phosphate
ion indirectly stimulates PTH secretion by forming complexes with
calcium in the serum. These complexes decrease the concentration
of ionized calcium, which is the form of calcium that binds to the
calcium-sensing receptor. In the kidney, high levels of calcium
and phosphate reduce calcitriol production and increase secalcifediolproduction.
Since calcitriol is far more potent than secalcifediol at increasing
serum calcium and phosphate, the net effect of calcitriol’s
action is feedback inhibition of vitamin D’s main action. Calcitriol
inhibits PTH secretion through a direct action on PTH gene transcription.
This provides yet another negative feedback loop because PTH is
a major stimulus for calcitriol production. The ability of calcitriol
to inhibit PTH secretion directly can be exploited by administering
analogs that have less effect on serum calcium. Such drugs are proving
useful in the management of the secondary hyperparathyroidism that
accompanies renal failure, and may be useful in selected cases of
Calcitonin is a peptide hormone secreted by the parafollicular
cells of the thyroid gland. The principal effect of calcitonin is
to lower serum calcium and phosphate by actions on bone and kidney (Figure
25–2). Calcitonin inhibits osteoclastic bone resorption.
During the initial stages of exogenous calcitonin administration,
bone formation is not impaired. However, with continued use, both
formation and resorption of bone are reduced. In the kidney, calcitonin
reduces resorption of a number of ions including calcium, phosphate,
sodium, potassium, and magnesium. Tissues other than bone and kidney
are also affected by calcitonin.
In pharmacologic dosages, calcitonin reduces gastric acid output
by inhibiting gastrin secretion, and increases secretion of sodium,
potassium, chloride, and water into the gut. Although calcitonin
does not significantly increase bone mass, it reduces the rate of
bone loss, making it a useful drug for the treatment of osteoporosis.
Its ability to block bone resorption and lower serum calcium also
make it useful for treating Paget’s disease and hypercalcemia.
Calcitonin is administered by injection or nasal spray.
These compounds were previously discussed (Chapter 22) in relation
to their regulation of sexual development, metabolic activity, and
reproduction. Estrogens and selective estrogen receptor modulators
(SERMs) such as tamoxifen or raloxifene prevent or delay bone loss
in postmenopausal women. However, long-term estrogen treatment increases
cardiovascular and cancer risks. Although it is not as effective
as estrogen at increasing bone density, raloxifene reduces bone
fractures and may reduce the risk of breast cancer.
The glucocorticoids have multiple influences on metabolism that
inhibit bone mineral maintenance (Chapter 23). Glucocorticoids alter
bone mineral homeostasis by antagonizing vitamin D–stimulated
intestinal calcium transport, stimulating renal calcium excretion,
and blocking bone formation. As a result, chronic systemic use of
glucocorticoids is a common cause of osteoporosis in adults and
stunted skeletal development in children. However, glucocorticoids
are useful in the intermediate-term treatment of hypercalcemia associated
with lymphomas and granulomatous diseases such as sarcoidosis.
A variety of other types of drugs are used to regulate bone mineral
homeostasis. The bisphosphonates were developed for that purpose.
The antibiotic plicamycin and the thiazide diuretics were developed
for other clinical uses, but have found clinical value in treating
disorders of bone mineral homeostasis.
The bisphosphonates (alendronate, etidronate,
ibandronate, pamidronate, risedronate, tiludronate, zoledronate) are
short-chain organic polyphosphate compounds that reduce both resorption
and formation of bone by acting on the basic hydroxyapatite crystal
structure of bone. The bisphosphonates have other complex cellular
effects, including inhibiting vitamin D production, inhibiting calcium
absorption from the gastrointestinal tract, and directly inhibiting
osteoclast function. In postmenopausal women, chronic bisphosphonate
therapy slows osteoporosis progression and reduces fractures. The
older drugs (etidronate, pamidronate) cause bone mineralization
defects and lose their effectiveness over a 12-month period. Alendronate
and risedronate cause fewer bone problems and are effective for
at least 5 years. These two drugs are commonly used for treating
postmenopausal and glucocorticoid-induced osteoporosis and for Paget’s
disease. Alendronate, used in combination with hormone replacement
therapy, further increases bone mass in postmenopausal patients.
Oral bioavailability of bisphosphonates is low (<10%),
and food impairs their absorption. Esophageal ulceration may also
occur. Patients should take these drugs with large quantities of
water, remain upright for 30 minutes, and avoid situations that
permit esophageal reflux (i.e., activities that increase intra-abdominal
pressure). In the prevention or treatment of osteoporosis, once-weekly
administration of a relatively large dose of a bisphosphonate is
as efficacious as daily administration of a smaller dose and does
not result in more toxicity. Annual intravenous administration of
zoledronate has similarly been found to be effective.
Appropriate concentrations of fluoride ion in drinking water
(0.5 to 1.0 ppm) or as an additive in toothpaste have a well-documented
ability to reduce dental caries. Chronic exposure to fluoride ion,
especially in high concentrations, may increase new bone synthesis.
What is not clear, however, is whether this new bone has normal
strength. Clinical trials of fluoride in patients with osteoporosis
have not demonstrated a reduced incidence of fractures. Acute fluoride
toxicity, usually caused by ingestion of rat poison, is manifested
by gastrointestinal and neurologic symptoms. Chronic toxicity (fluorosis)
includes ectopic bone formation (exostoses) and calcified bumps
This drug class was previously discussed in relation to the treatment
of hypertension (Chapter 7). Thiazides increase the effectiveness
of parathyroid hormone in stimulating renal reabsorption of calcium.
In the distal tubule, thiazides block sodium reabsorption at the
luminal surface. The resultant fall in intracellular sodium causes
a greater calcium-sodium exchange at basolateral membranes, bringing
sodium into distal tubule cells and transporting calcium out into
the interstitial space. The net effect of thiazide diuretics is
enhanced renal calcium reabsorption. Thiazides are useful in reducing
hypercalciuria and nephrolithiasis in subjects with idiopathic
hypercalciuria. They are not used to treat osteoporosis.
This antibiotic is used to reduce serum calcium and bone resorption
in Paget’s disease and hypercalcemia. Because of the risk
of complications, such as thrombocytopenia, hemorrhage, and hepatic
and renal damage, plicamycin is not commonly prescribed. The drug
is mainly restricted to short-term treatment of serious hypercalcemia.