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Abstract
Objective
This paper describes the rationale and supporting data for once-weekly dosing of alendronate.
Background
Alendronate sodium, a bisphosphonate that potently inhibits bone resorption, has been
shown to increase bone mass and substantially reduce the incidence of osteoporotic
fractures, including fractures of the hip. The standard regimen of daily administration
has generally been well tolerated. However, weekly administration may provide greater
convenience to patients without compromising efficacy or tolerability. The pharmacokinetics
of alendronate and bone remodeling theory predict similar efficacy for weekly and
daily administration if the cumulative dose is the same. Bone resorption in individual
remodeling units normally proceeds for ~2 weeks; alendronate inhibits the rate and
extent of resorption. Because the half-life of residence on bone surfaces is several
weeks, weekly administration of alendronate should inhibit bone resorption to an overall
extent similar to that of daily dosing, thereby producing similar effects on bone
mass and strength. Animal studies demonstrate that both weekly and daily parenteral
administration of alendronate effectively increase bone mass and strength, but confirmation
of efficacy is needed for weekly oral dosing in humans. Although daily bisphosphonates
(alendronate and risedronate) elicited esophageal irritation in a canine model of
gastroesophageal reflux, weekly dosing with alendronate at a higher unit dose did
not. Thus, the lower frequency of weekly dosing with a higher unit dose may actually
reduce the risk of upper gastrointestinal irritation compared with daily administration
of a lower dose.
Conclusions
Current safety and efficacy data justify further investigation of once-weekly dosing
of alendronate. Two positive-control, double-blind, randomized trials of osteoporosis
treatment and prevention are currently being performed to assess the comparability
of weekly, biweekly, and daily dosing of alendronate with regard to effects on bone
density, safety, and tolerability.
Key words
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References
- Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis.N Engl J Med. 1995; 333: 1437-1443
- Alendronate prevents postmenopausal bone loss in women without osteoporosis: A double-blind, randomized, controlled trial.Ann Intern Med. 1998; 128: 253-261
- Prevention of bone loss with alendronate in postmenopausal women under 60 years of age.N Engl J Med. 1998; 338: 485-492
- Skeletal benefits of two years of alendronate treatment are similar for early post-menopausal Asian and Caucasian women.Osteoporosis Int. 1999; 9: 455-460
- Effect of alendronate sodium on bone mineral density in postmenopausal, osteoporotic black women of African-American descent.J Bone Miner Res. 1999; 14 (Abstract): S278
- Alendronate for the prevention and treatment of glucocorticoidinduced osteoporosis.N Engl J Med. 1998; 339: 292-299
- Alendronate treatment of osteoporosis in men.J Bone Miner Res. 1999; 14 (Abstract): S184
- Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: Results of the FOSIT study.Osteoporosis Int. 1999; 9: 461-468
- Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.Lancet. 1996; 348: 1535-1541
- Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial.JAMA. 1998; 280: 2077-2082
- Consistency of effect of alendronate on reduction in risk of nonvertebral fractures.Bone. 1998; 23 (Abstract): S478
- Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone.J Clin Endocrinol Metab. 1996; 81: 961-967
- Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: A randomized, placebo-controlled trial.Am J Med. 1996; 101: 341-348
- Alendronate for treatment of osteoporosis in elderly female long-term care facility residents.J Bone Miner Res. 1999; 14 (Abstract): S279
- Safety and efficacy of alendronate for the treatment of osteoporosis in pediatric rheumatic diseases.Arthritis Rheum. 1999; 42 (Suppl) (Abstract): S400
- Alendronate reduces the risk of multiple clinical fractures: Results from FIT.J Bone Miner Res. 1999; 14 (Abstract): S527
- The effect of alendronate on fracture-related healthcare utilization and costs: The Fracture Intervention Trial.Bone. 1998; 23 (Abstract): S182
- The impact of alendronate on height loss in women with and without existing vertebral fractures: The Fracture Intervention Trial.Osteoporosis Int. 1998; 8 (Abstract): 107
Nevitt M, Thompson D, Black D, et al. Effect of alendronate on functional limitation caused by back pain in postmenopausal women with existing vertebral fractures. Arch Intern Med. In press.
- The clinical tolerability profile of alendronate.Int J Clin Pract. 1999; : 51-61
- Esophagitis associated with the use of alendronate.N Engl J Med. 1996; 335: 1016-1021
- Esophagitis and alendronate.N Engl J Med. 1996; 335 (Letter): 1069-1070
- Textbook of Osteoporosis. Blackwell Science Ltd, Oxford1996: 1-28
- Textbook of Osteoporosis. Blackwell Science Ltd, Oxford1996: 308-367
- Reconstruction of the formative site in iliac trabecular bone in 20 normal individuals employing a kinetic model for matrix and mineral apposition.Metab Bone Dis Relat Res. 1984; 5: 243-252
Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive treatments are related to changes in bone density. J Clin Endocrinol Metab. In press.
- Pharmacokinetics of alendronate: An overview.Int J Clin Pract Suppl. 1999; : 18-26
- Pharmacokinetics of alendronate.Clin Pharmacokinet. 1999; 36: 315-328
- The bisphosphonate alendronate (MK-217) inhibits bone loss due to ovariectomy in rats.J Bone Miner Res. 1991; 6: 339-346
- The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates.J Clin Invest. 1993; 92: 2577-2586
- Preclinical pharmacology of alendronate.Osteoporosis Int. 1993; 3: S7-S12
- Osteopenia in the immobilized rat hind limb is associated with increased bone resorption and decreased bone formation.Bone. 1989; 10: 187-194
- Aminohydroxybutane bisphosphonate inhibits bone loss due to immobilization in rats.J Bone Miner Res. 1990; 5: 279-286
- The effects of the aminobisphosphonate alendronate on thyroid hormoneinduced osteopenia in rats.Calcif Tissue Int. 1993; 53: 278-282
- The aminobisphosphonate alendronate inhibits bone loss induced by thyroid hormone in the rat: Comparison between effects on tibiae and vertebrae.Bone. 1993; 14: 499-504
- Effects of the bisphosphonate tiludronate on bone resorption, calcium balance, and bone mineral density.J Bone Miner Res. 1993; 8: 1491-1498
- IGF-I and pamidronate increase bone mineral density in ovariectomized adult rats.Am J Physiol. 1993; 265: E770-E776
- Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis.N Engl J Med. 1990; 322: 1265-1271
- Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: Three years of blinded therapy followed by one year of open therapy.Am J Med. 1993; 95: 557-567
- Two years' effectiveness of intravenous pamidronate (APD) versus oral fluoride for osteoporosis occurring in the postmenopause.Osteoporosis Int. 1994; 4: 76-83
- Intermittent treatment with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) in the therapy of postmenopausal osteoporosis.Bone Miner. 1991; 15: 237-248
- Intravenous administration of alendronate counteracts the in vivo effects of glucocorticoids on bone remodeling.Calcif Tissue Int. 1996; 58: 166-169
- Adverse effects of bisphosphonates: A comparative review.Drug Saf. 1996; 14: 158-170
- Risedronate increases bone mass in an early postmenopausal population: Two years of treatment plus one year of follow-up.J Clin Endocrinol Metab. 1998; 83: 396-402
- Three monthly intravenous injections of ibandronate in the treatment of postmenopausal osteoporosis.Am J Med. 1997; 103: 298-307
- Intramuscular clodronate therapy in postmenopausal osteoporosis.Bone. 1999; 24: 125-129
- Chronic intermittent cyclical administration of tiludronate in postmenopausal osteoporosis: Report of two multicenter studies in 2316 patients.Bone. 1998; 23 (Suppl) (Abstract): S175
- Intermittent cyclical low dose tiludronate in treatment of postmenopausal osteoporosis. Report of two phase III European studies (2305 patients).Bone. 1998; 23 (Suppl) (Abstract): S594
- Monitoring bone resorption in early post-menopausal women by an immunoassay for cross-linked collagen peptides in urine.J Bone Miner Res. 1994; 9: 135-142
- ActonelM [package insert]. Procter & Gamble Pharmaceuticals, Cincinnati, Ohio1998
- Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis.J Bone Miner Res. 1997; 12: 1700-1707
- Keratinocyte model for bisphosphonate esophageal irritation: Inhibition of cell growth by combined inhibition of protein prenylation and sterol synthesis.J Bone Miner Res. 1999; 14 (Abstract): S406
Bauer D, Black D, Freedholm D, et al. Upper gastrointestinal safety profile of alendronate: The Fracture Intervention Trial. Arch Intern Med. In press.
- Comparative study of potential for bisphosphonates to damage gastric mucosa of rats.Dig Dis Sci. 1998; 43: 1009-1015
- Esophageal irritation due to alendronate sodium tablets: Possible mechanisms.Dig Dis Sci. 1998; 43: 1998-2002
- Lineage commitment and maturation of epithelial cells in the gut.Front Biosci. 1999; 4: D286-D298
- Alendronate in the treatment of Paget's disease of bone.Bone. 1997; 20: 263-271
- Alendronate treatment of the postmenopausal osteoporotic woman: Effect of multiple dosages on bone mass and bone remodeling.Am J Med. 1995; 99: 144-152
Article info
Publication history
Accepted:
December 14,
1999
Identification
Copyright
© 2000 Published by Elsevier Inc.
