Alendronate (Fosamax®)
Alendronate
Fosamax®
Classification:
Electrolytic and Renal Agents
Musculoskeletal Agents
- Bone Resorption Inhibitors
Description: Alendronate is a second-generation bisphosphonate but was the first member of this group that strengthens bone, compared to simply preventing bone loss. Alendronate is a more potent inhibitor of bone resorption than the first generation agent etidronate however, unlike etidronate, the effective dose of alendronate does not inhibit bone mineralization. In humans, a 10 mg oral dose of alendronate is as effective as about 1500 mg of etidronate at reducing hypercalcemia in tumor-induced bone disease. Alendronate was granted final FDA approval for the treatment of osteoporosis in postmenopausal women and for the treatment of Paget’s disease on September 29, 1995. The drug was subsequently approved for the prevention of osteoporosis in postmenopausal women and for the treatment of corticosteroid-induced osteoporosis. In October 2001, a once-weekly dosage form of Fosamax® was approved by the FDA for the treatment and prevention of osteoporosis. Fosamax® oral solution, a once-weekly formulation that is bioequivalent to the once-weekly tablets, was approved by the FDA in September 2003. Alendronate is under investigation for the treatment of hypercalcemia associated with malignancy and heterotopic ossification.
Mechanism of Action: As with other bisphosphonates, alendronate inhibits osteoclast activity and bone resorption. By binding to calcium salts, alendronate blocks the transformation of calcium phosphate into hydroxyapatite and inhibits the formation, aggregation, and dissolution of hydroxyapatite crystals in bone. While inhibition of hydroxyapatite crystals may lead to the inhibition of bone mineralization seen at high doses, it does not explain alendronate’s effects on bone resorption. The mechanism of inhibition of bone resorption by bisphosphonates is not known. Alendronate is preferentially localized to the site of resorption; however, alendronate does not interfere with the recruitment and attachment of osteoclasts. Alendronate is internalized by osteoclasts causing disruption of osteoclast cytoskeleton, loss of the ruffled border, which may lead to the loss of ability to resorb bone. The exact molecular mechanisms of these effects are not known. In addition, macrophages and osteoblasts may mediate the antiresorptive effects of bisphosphonates. Alendronate inhibits the production of interleukin (IL)-1beta, IL-6 and TNF by monocytes. Continuous administration of alendronate is necessary to maintain osteoclast suppression on newly-formed resorption surfaces.
In patients with Paget’s disease, alendronate directly decreases bone resorption, resulting in a significant decrease in serum alkaline phosphatase and urinary markers of bone collagen degradation. Alendronate also slightly increases parathyroid hormone levels. Alendronate significantly increases bone mineral density in women with postmenopausal osteoporosis. Increases in bone mass of the spine and hip are evident after three months, and do not occur at the expense of other skeletal bone. Continuous therapy is necessary to maintain increases in bone mass. Histological examination after at least one year’s therapy, reveals that bone formation is of normal structure and mineral content. In a short trial, alendronate decreased serum alkaline phosphatase up to 12 weeks post treatment and serum osteocalcin up to 30 weeks post treatment. These reductions were found to be dose-dependent. Alendronate produces a significant decrease in serum calcium and urinary calcium levels in patients with hypercalcemia of malignancy. It prevents progression of osteolytic disease and alleviates severe bone pain. Comparative studies with clodronate indicated that alendronate was more effective than clodronate in malignant hyperosteolysis.
Pharmacokinetics: Alendronate is administered orally. Absorption is poor, with oral bioavailability of less than 1%. This becomes almost negligible if alendronate is taken within 2 hours of breakfast. Even orange juice or coffee can reduce bioavailability by about 60%. To achieve maximum possible bioavailability, alendronate must be taken in the fasting state and at least 2 hours before a standard breakfast. Cations (e.g., calcium, magnesium) reduce bioavailability. Transient distribution into soft tissue is rapidly followed by redistribution to bone or urinary excretion. Alendronate is approximately 78% bound to protein in human plasma. There is no evidence that any metabolism takes place. Elimination from plasma is rapid, falling 95% within 6 hours of an IV dose. Approximately 50% of a single IV dose is excreted in the urine within 72 hours. Once alendronate is bound to bone, the half-life is more than 10 years. Inhibition of bone resorption diminishes after completion of treatment, suggesting that not all the alendronate sequestered in bone is biologically active. Estimations suggest that the amount of alendronate released from the skeleton daily, after 10 years of daily dosing with 10 mg of alendronate, is 25% of that absorbed from the GI tract.
Bone resorption in individual remodeling units normally continues for approximately 2 weeks. Due to the long half-life of alendronate in the bone, weekly administration of alendronate should inhibit bone resorption and provide benefits on bone mass and strength to a similar extent as daily administration.
Fosamax Tablets(Tab 5 mg) 
Special Populations: The elimination of alendronate in animals with renal impairment is reduced. Although clinical data does not exist, it is likely that elimination of alendronate in patients with renal insufficiency will also be reduced. Therefore, somewhat greater accumulation of alendronate in the bone of patients with renal impairment may occur. Alendronate is not recommended for use in patients with a CrCl of < 35 ml/min due to a lack of experience and insufficient data in this population. The bioavailability of single doses of alendronate 35 mg or 70 mg in children 4 - 16 years of age with osteogenesis imperfecta is less than 0.6%, which is comparable to the bioavailability of alendronate in adults.
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References
. Fleisch H. New biphosphonates in osteoporosis. Osteoporosis Int. 1993;(suppl 2):S15 - S22.
. Fleisch H. Biphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcemic and metastatic bone disease. Drugs. 1991;42:919 - 44.
. Anon. Alendronate. Phase III Drug Profiles 1994;4:3 - 9.
. Harris ST, Gertz BJ, et al. The effects of short term treatment with alendronate on vertebral density and biochemical markers of bone remodeling in early postmenopausal women. J Clin Endocrinol Metab 1993;76:1399 - 1406.
. Rizzoli R, Buchs B, Bonjour J-P. Effect of a single infusion of alendronate in malignant hypercalcemia; dose dependency and comparison with clodronate. Int J Cancer 1992;50:706 - 12.
. Attardo-Parrinello G, Merlini G, et al. Effects of a new aminodiphosphonate (aminohydroxybutylidene diphosphonate) in patients with osteolytic lesions from metastases and myelomatosis. Arch Intern Med 1987;147:1629 - 33.
. Bone HG, Adami S, Rizzoli R, et al. Weekly administration of alendronate: rationale and plan for clinical assessment. Clin Ther 2000;22:15 - 28.
. Lourwood DL. The pharmacology and therapeutic utility of bisphosphonates. Pharmacotherapy 1998;18:779 - 89.
[ Revised 3/7/2006 3:05:00 PM ]
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