DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1294 uses of vitamin D are discovered, it will become important to
develop noncalcemic analogs of calcitriol that achieve effects on cellular
differentiation without the risk of hypercalcemia.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Adverse Effects of Vitamin D Therapy
The primary toxicity associated with calcitriol reflects
its potent effect to increase intestinal calcium and phosphate
absorption, along with the potential to mobilize
osseous calcium and phosphate. Hypercalcemia, with
or without hyperphosphatemia, commonly complicates
calcitriol therapy and may limit its use at doses that
effectively suppress PTH secretion. As described earlier,
noncalcemic vitamin D analogs provide alternative
interventions, although they do not obviate the need to
monitor serum calcium and phosphorus concentrations.
Hypervitaminosis D is treated by immediate withdrawal of
the vitamin, a low-calcium diet, administration of glucocorticoids,
and vigorous fluid support. As noted earlier under hypercalcemia,
forced saline diuresis with loop diuretics is also useful. With this
regimen, the plasma Ca 2+ concentration falls to normal, and Ca 2+ in
soft tissue tends to be mobilized. Conspicuous improvement in renal
function occurs unless renal damage has been severe.
CALCITONIN
Diagnostic Uses of Calcitonin. Calcitonin is a sensitive
and specific marker for the presence of medullary thyroid
carcinoma (MTC), a neuroendocrine malignancy
originating in thyroid parafollicular C cells. MTC can
be hereditary (25%) or sporadic (75%) and is present
in all patients with the multiple endocrine neoplasia
type 2 (MEN2) syndromes. Because one form of
MEN2 is inherited as a dominant trait, relatives of
patients should be examined repeatedly by calcitonin
measurements from early childhood. Because calcitonin
levels may be low in early tumor stages or in premalignant
C-cell hyperplasia, pentagastrin-induced
calcitonin provides greater sensitivity and increased
MTC detection. The identification of discrete mutations
in the RET protooncogene in subjects with MEN2
offers hope that genetic screening will supplant reliance
on testing serum calcitonin, which can give spurious
results.
Therapeutic Uses. Calcitonin lowers plasma Ca 2+ and
phosphate concentrations in patients with hypercalcemia;
this effect results from decreased bone resorption
and is greater in patients in whom bone turnover
rates are high. Although calcitonin is effective for up to
6 hours in the initial treatment of hypercalcemia,
patients become refractory after a few days. This is
likely due to receptor downregulation (Takahashi et al.,
1995). Use of calcitonin does not substitute for aggressive
fluid resuscitation, and the bisphosphonates are the
preferred agents.
Calcitonin is effective in disorders of increased skeletal
remodeling, such as Paget’s disease, and in some patients with osteoporosis.
In Paget’s disease, chronic use of calcitonin produces longterm
reductions of serum alkaline phosphatase activity and
symptoms. Development of antibodies to calcitonin occurs with prolonged
therapy, but this is not necessarily associated with clinical
resistance. Side effects of calcitonin include nausea, hand swelling,
urticaria, and, rarely, intestinal cramping. Side effects appear to
occur with equal frequency with human and salmon calcitonin.
Salmon calcitonin is approved for clinical use. The latter product
also is available as a nasal spray, introduced for once-daily treatment
of postmenopausal osteoporosis. For Paget’s disease, calcitonin generally
is administered by subcutaneous injection because intranasal
delivery is relatively ineffective owing to limited bioavailability.
After initial therapy at 100 units/day, the dose typically is reduced to
50 units three times a week.
BISPHOSPHONATES
Bisphosphonates are analogs of pyrophosphate (Figure
44–11) that contain two phosphonate groups attached to
a geminal (central) carbon that replaces the oxygen in
pyrophosphate. Because they form a three-dimensional
structure capable of chelating divalent cations such as
Ca 2+ , the bisphosphonates have a strong affinity for
bone, targeting especially bone surfaces undergoing
remodeling. Accordingly, they are used extensively in
conditions characterized by osteoclast-mediated bone
resorption, including osteoporosis, steroid-induced
osteoporosis, Paget’s disease, tumor-associated osteolysis,
breast and prostate cancer, and hypercalcemia.
Calcium supplements, antacids, food or medications
containing divalent cations, such as iron, may interfere
with intestinal absorption of bisphosphonates. Recent
evidence suggests that second- and third-generation bisphosphonates
also may be effective anticancer drugs.
For a review of the basic and clinical pharmacology of
bisphosphonates, see Russell, 2007.
The clinical utility of bisphosphonates resides in their direct
inhibition of bone resorption. First-generation bisphosphonates contain
minimally modified side chains (R 1
and R 2
in Figure 44-11)
(medronate, clodronate, and etidronate) or posses a chlorophenol
group (tiludronate) (Figure 44-11). They are the least potent and in
some instances cause bone demineralization. Second-generation
aminobisphosphonates (e.g., alendronate and pamidronate) contain
a nitrogen group in the side chain. They are 10-100 times more
potent than first-generation compounds. Third-generation bisphosphonates
(e.g., risedronate and zoledronate) contain a nitrogen atom
within a heterocyclic ring and are up to 10,000 times more potent
than first-generation agents.