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

1296 has been supplanted largely by pamidronate and zoledronate for
treating hypercalcemia. Pamidronate (AREDIA) is approved for management
of hypercalcemia and for prevention of bone loss in breast
cancer and multiple myeloma, but it also is effective in other skeletal
disorders. Pamidronate is available in the U.S. only for parenteral
administration. For treatment of hypercalcemia, pamidronate may
be given as an intravenous infusion of 60-90 mg over 4-24 hours.
Several newer bisphosphonates have been approved for treatment
of Paget’s disease. These include tiludronate (SKELID), alendronate
(FOSAMAX), and risedronate (ACTONEL). Tiludronate is
approved for treatment of Paget’s disease of bone. Standard dosing
is 400 mg/day orally for 3 months. Tiludronate in recommended
doses does not interfere with bone mineralization, unlike etidronate.
Zoledronate (ZOMETA) is approved for treating Paget’s disease and
administered as a single 5-mg infusion decreased bone turnover
markers for 6 months with no loss of therapeutic effect (Reid et al.,
2005). Zometa is widely used for prevention of osteoporosis in
prostate and breast cancer patients receiving hormonal therapy. It is
also approved for treating hypercalcemia of malignancies and for
preventing fractures and skeletal complications in cancer patients
with bone metastases. It is widely used to prevent osteoporosis and
fractures in breast and prostate cancer patients receiving hormoneantagonist
treatment.
The potent bisphosphonate ibandronate is approved for the
prevention and treatment of postmenopausal osteoporosis. The recommended
oral dose is 2.5 mg daily or 150 mg once monthly, which
appears to be as effective as daily treatment and is well tolerated.
Absorption, Fate, and Excretion. All oral bisphosphonates are very
poorly absorbed from the intestine and have remarkably limited
bioavailability (<1% [alendronate, risedronate] to 6% [etidronate,
tiludronate]). Hence these drugs should be administered with a full
glass of water following an overnight fast and at least 30 minutes
before breakfast. Oral bisphosphonates have not been used widely in
children or adolescents because of uncertainty of long-term effects
of bisphosphonates on the growing skeleton.
Bisphosphonates are excreted primarily by the kidneys.
Adjusted doses for patients with diminished renal function have not
been determined; bisphosphonates currently are not recommended
for patients with a creatinine clearance of <30 mL/minute.
Adverse Effects. Oral bisphosphonates, including alendronate, ibandronate,
and risedronate, can cause heartburn, esophageal irritation,
or esophagitis. Other GI side effects include abdominal pain and
diarrhea. Symptoms often abate when patients take the medication
after an overnight fast, with tap or filtered water (not mineral water),
and remain upright. Esophageal complications are infrequent when
the drug is taken as described. If symptoms persist despite these
precautions, use of a nonsteroidal anti-inflammatory drug or acetaminophen
can diminish these symptoms; a proton pump inhibitor at
bedtime may be helpful (Chapter 45). Both drugs may be better tolerated
on a once-weekly regimen with no reduction of efficacy.
Patients with active upper GI disease should not be given oral bisphosphonates.
Serious osteonecrosis of the jaw is associated with use of bisphosphonates
(Edwards et al., 2008). In 2008 the FDA issued an
alert on the use of bisphosphonates (http://www.fda.gov/Drugs/
DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvid
ers/ucm124165.htm) and product labeling was modified to highlight
SECTION V
HORMONES AND HORMONE ANTAGONISTS
the severe musculoskeletal pain that may occur and its relation to
osteonecrosis of the jaw.
Owing to cytokine release, initial parenteral infusion of
pamidronate, may cause skin flushing, flu-like symptoms, muscle
and joint aches and pains, nausea and vomiting, abdominal discomfort
and diarrhea (or constipation) but mainly when given in higher
concentrations or at faster rates than those recommended. These
symptoms are short lived and generally do not recur with subsequent
administration.
Zoledronate has more potent effects on calcium than some
other bisphosphonates and is capable of causing severe hypocalcemia.
It has been associated with renal toxicity, deterioration of
renal function, and potential renal failure. Thus, the infusion should
be given over at least 15 minutes, and the dose should be 4 mg.
Patients who receive zoledronate should have standard laboratory
and clinical parameters of renal function assessed prior to treatment
and periodically after treatment to monitor for deterioration in renal
function.
Other Therapeutic Uses
Hypercalcemia. The use of pamidronate in the management of malignancy-associated
hypercalcemia was described earlier. Zoledronate
appears to be more effective than pamidronate and at least as safe,
can be infused over 15 minutes rather than 2-4 hours, and is FDAapproved
for this indication.
Postmenopausal Osteoporosis. Much interest is focused on the role of
bisphosphonates in the treatment of osteoporosis. Clinical trials show
that treatment is associated with increased bone mineral density and
protection against fracture.
Cancer. Bisphosphonates may also have direct antitumor action by
inhibiting oncogene activation and through their anti-angiogenic
effects. Randomized clinical trials of bisphosphonates in patients
with breast cancer suggest that they delay or prevent development of
metastases as a component of endocrine adjuvant therapy (Gnant
et al., 2009).
PARATHYROID HORMONE
Continuous administration of parathyroid hormone
(PTH) or high-circulating PTH levels achieved in primary
hyperparathyroidism causes bone demineralization
and osteopenia. However, intermittent PTH administration
promotes bone growth. Selye first described the
anabolic action of PTH some 80 years ago, but this
observation was largely ignored and generally forgotten.
Beginning in the 1970s, studies focused on the anabolic
action of PTH, culminating with FDA approval of synthetic
human 34-amino-acid amino-terminal PTH fragment
[hPTH(1-34), teriparatide (FORTEO)] for use in
treating severe osteoporosis (Hodsman et al., 2005).
Full-length human recombinant PTH(1-84) is in phase III trials
for hypoparathyroidism, for which teriparatide is not approved.
Intermittent PTH(1-84) may soon be approved for use in osteoporosis,
but its benefits over PTH(1-34) remain to be established.