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

alendronate to PTH treatment provided no additional benefit for
BMD and reduced the anabolic effect of PTH in both women and
men (Cosman, 2008). Sequential treatment with PTH(1-84) followed
by alendronate increased vertebral BMD to a greater degree than
alendronate or estrogen alone (Rittmaster et al., 2000). Recent work
underscores the beneficial action of alendronate in consolidating the
gains in lumbar spine BMD achieved by antecedent teriparatide
treatment in men.
The fracture outcome 30 months after cessation of teriparatide
therapy was studied in a cohort of patients included in the FPT.
Approximately 50% of each group (teriparatide or control) were
treated with a bisphosphonate for some period of time during the 30-
month period. Patients treated with bisphosphonates after discontinuation
of teriparatide showed continued increments in BMD, whereas
those who received no treatment had declines (Prince et al., 2005).
Paget’s Disease. Although most patients with Paget’s disease require
no treatment, factors such as severe pain, neural compression, progressive
deformity, hypercalcemia, high-output congestive heart failure,
and repeated fracture risk are considered indications for
treatment. Bisphosphonates and calcitonin decrease the elevated biochemical
markers of bone turnover, such as plasma alkaline phosphatase
activity and urinary excretion of hydroxyproline. An initial
course of bisphosphonate typically is given once daily or once weekly
for 6 months. With treatment, most patients experience a decrease in
bone pain over several weeks. Such treatment may induce long-lasting
remission. If symptoms recur, additional courses of therapy can
be effective. When etidronate is given at higher doses (10-20 mg/kg
per day) or continuously for >6 months, there is a substantial risk for
osteomalacia. At lower doses (5-7.5 mg/kg per day), focal osteomalacia
has been observed occasionally. Defective mineralization has
not been observed with other bisphosphonates or with calcitonin.
Choice of optimal therapy for Paget’s disease varies among
patients. Bisphosphonates are the standard therapy. Intravenous
pamidronate induces long-term remission following a single infusion.
Zoledronate seems to exhibit greater response rates and a
longer median duration of complete response (Major et al., 2001).
Compared with calcitonin, bisphosphonates have the advantage of
oral administration, lower cost, lack of antigenicity, and generally
fewer side effects. Resistance to calcitonin develops in most patients.
However, calcitonin is highly reliable and may have a distinct skeletal
analgesic property. Mithramycin (plicamycin) has been used in
difficult cases of Paget’s disease that do not respond to bisphosphonates
or calcitonin. Therapeutic utility of this agent is limited by a
high potential for hemorrhagic and other toxicities, and it is not
generally recommended.
FLUORIDE
Fluoride is discussed because of its toxic properties and
its effect on dentition and bone.
Absorption, Distribution, and Excretion. Human beings obtain
fluoride predominantly from the ingestion of plants and water, with
most absorption taking place in the intestine. The degree of fluoride
absorption correlates with its water solubility. Relatively soluble
compounds, such as sodium fluoride, are absorbed almost completely,
whereas relatively insoluble compounds, such as cryolite
(Na 3
AlF 6
) and the fluoride found in bone meal (fluoroapatite) are
absorbed poorly. A second route of absorption is through the lungs,
and inhalation of fluoride present in dusts and gases constitutes the
major route of industrial exposure.
Fluoride is distributed widely in organs and tissues but is concentrated
in bone and teeth, and the skeletal burden is related to
intake and age. Bone deposition reflects skeletal turnover; growing
bone shows greater deposition than mature bone.
The kidneys are the major site of fluoride excretion. Small
amounts of fluoride also appear in sweat, milk, and intestinal secretions;
in a very hot environment, sweat can account for nearly 50%
of total fluoride excretion.
Pharmacological Actions and Uses. Because it is concentrated in
the bone, the radionuclide 18 F has been used in skeletal imaging.
Sodium fluoride enhances osteoblast activity and increases bone volume.
These effects may be bimodal, with low doses stimulating and
higher doses suppressing osteoblasts; if true, this may account for the
poorly mineralized and mechanically defective bone seen in some
studies. In doses of 30-60 mg/day, fluoride increases trabecular bone
mineral density in many, but not all, patients. In one controlled trial,
fluoride increased lumbar spine density (cancellous bone) but
decreased cortical bone mineral density; these changes were associated
with a significant increase in peripheral fractures and stress fractures
(Riggs et al., 1990). In one study, sustained-release fluoride,
which provided lower blood fluoride levels, increased bone mineral
density and decreased fractures (Pak et al., 1994). Intermittent
courses of slow-release fluoride also have been evaluated. When the
total fluoride dose was kept constant (Balena et al., 1998), there was
no difference in outcome between continuous and intermittent fluoride
treatment; notably, both regimens increased cancellous and trabecular
thickness to the same extent. Unfortunately, increased bone
mass is not synonymous with increased bone strength (Riggs et al.,
1990). Thus, the apparent effects of fluoride in osteoporosis are
slight compared with those achieved with PTH or other agents.
Other pharmacological actions of fluoride can be classified as
toxic. Fluoride inhibits several enzyme systems and diminishes tissue
respiration and anaerobic glycolysis.
Acute Poisoning. Acute fluoride poisoning usually results from
accidental ingestion of fluoride-containing insecticides or rodenticides.
Initial symptoms (salivation, nausea, abdominal pain, vomiting,
and diarrhea) are secondary to the local action of fluoride on
the intestinal mucosa. Systemic symptoms are varied and severe:
increased irritability of the central nervous system consistent with
the Ca 2+ -binding effect of fluoride and the resulting hypocalcemia;
hypotension, presumably owing to central vasomotor depression as
well as direct cardiotoxicity; and stimulation and then depression of
respiration. Death can result from respiratory paralysis or cardiac
failure. The lethal dose of sodium fluoride for humans is ~5 g,
although there is considerable variation. Treatment includes the
intravenous administration of glucose in saline and gastric lavage
with lime water (0.15% calcium hydroxide solution) or other Ca 2+
salts to precipitate the fluoride. Calcium gluconate is given intravenously
for tetany; urine volume is kept high with vigorous fluid
resuscitation.
Chronic Poisoning. In humans, the major manifestations of chronic
ingestion of excessive fluoride are osteosclerosis and mottled
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CHAPTER 44
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER