Pharmacokinetics of Alendronate
Review Article Drug Disposition
First Online: 13 September 2012 DOI:
Cite this article as: Porras, A.G., Holland, S.D. & Gertz, B.J. Clin Pharmacokinet (1999) 36: 315. doi:10.2165/00003088-199936050-00002 Abstract
Alendronate (alendronic acid; 4-amino-1-hydroxybutylidene bisphosphonate) has demonstrated effectiveness orally in the treatment and prevention of postmenopausal osteoporosis, corticosteroid-induced osteoporosis and Paget’s disease of the bone. Its primary mechanism of action involves the inhibition of osteoclastic bone resorption. The pharmacokinetics and pharmacodynamics of alendronate must be interpreted in the context of its unique properties, which include targeting to the skeleton and incorporation into the skeletal matrix.
Preclinically, alendronate is not metabolised in animals and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although soon after administration the drug distributes widely in the body, this transient state is rapidly followed by a nonsaturable redistribution to skeletal tissues. Oral bioavailability is about 0.9 to 1.8%, and food markedly inhibits oral absorption. Removal of the drug from bone reflects the underlying rate of turnover of the skeleton. Renal clearance appears to involve both glomerular filtration and a specialised secretory pathway.
Clinically, the pharmacokinetics of alendronate have been characterised almost exclusively based on urinary excretion data because of the extremely low concentrations achieved after oral administration. After intravenous administration of radiolabelled alendronate to women, no metabolites of the drug were detectable and urinary excretion was the sole means of elimination. About 40 to 60% of the dose is retained for a long time in the body, presumably in the skeleton, with no evidence of saturation or influence of one intravenous dose on the pharmacokinetics of subsequent doses.
The oral bioavailability of alendronate in the fasted state is about 0.7%, with no significant difference between men and women. Absorption and disposition appear independent of dose. Food substantially reduces the bioavailability of oral alendronate; otherwise, no substantive drug interactions have been identified.
The pharmacokinetic properties of alendronate are evident pharmacodynamically. Alendronate treatment results in an early and dose-dependent inhibition of skeletal resorption, which can be followed clinically with biochemical markers, and which ultimately reaches a plateau and is slowly reversible upon discontinuation of the drug. These findings reflect the uptake of the drug into bone, where it exerts its pharmacological activity, and a time course that results from the long residence time in the skeleton. The net result is that alendronate corrects the underlying imbalance in skeletal turnover characteristic of several disease states. In women with postmenopausal osteoporosis, for example, alendronate treatment results in increases in bone mass and a reduction in fracture incidence, including at the hip.
Russell RG, Rogers MJ. Introduction to bisphosphonates and the clinical pharmacology of alendronate. Br J Rheumatol. 1997; 36: 10–4.
Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998; 19(1): 80–100.
Fleisch H, Russell RG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature. 1966; 212: 901–3.
Nussbaum S, Warrell R, Rude R, et al. Treatment of cancer-associated hypercalcemia with alendronate (aminohydroxbutylidene bisphosphonate) [abstract]. Proc Am Soc Clin Oncol. 1992; 11: 377.
Warrell R, Mullane M, Bilezikian J, et al. Treatment of cancer-associated hypercalcemia with alendronate sodium: a randomized double-blind comparison with etidronate [abstract]. Proc Am Soc Clin Oncol. 1993; 12: A1514.
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.
Kanis JA, Gertz BJ, Singer F, et al. Rationale for the use of alendronate in osteoporosis. Osteoporosis Int. 1995; 5(1): 1–13.
Liberman UA, Weiss SR, Broil J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 1995; 333: 1437–43.
Chestnut CH, McClung MR, Ensrud KE, et al. Alendronate treatment of postmenopausal osteoporotic women: effect of multiple dosages on bone mass and bone remodeling. Am J Med. 1995; 99: 144–52.
Black DM, Cummings SR, Karpf DB, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996; 348: 1535–41.
Devogelaer JP, Broil H, Correa-Rotter R, et al. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone. 1996; 18(2): 141–50.
Stock JL, Bell NH, Chestnut CH, et al. Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med. 1997; 103: 291–7.
Karpf DB, Shapiro DR, Seeman E, et al. Prevention of nonvertebral fractures by alendronate. JAMA. 1997; 277(14): 1159–64.
Saag KG, Emkey R, Schnitzer TJ, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med. 1998; 339: 292–9.
Burssens A, Gertz BJ, Francis RM, et al. A double-blind, placebo controlled, rising multiple dose trial of oral alendronate in Paget’s disease. J Bone Miner Res. 1990; 5 Suppl. 2: S239.
Khan SA, Vasikaran S, McCloskey EV, et al. Alendronate in the treatment of Paget’s disease of bone. Bone. 1997; 20(3): 263–71.
Siris E, Weinstein RS, Altaian R, et al. Comparative study of alendronate versus etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab. 1996; 81(3): 961–7.
Reid IR, Nicholson GC, Weinstein RS, et al. Biochemical and radiologic improvement in Paget’s disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med. 1996; 171(4): 341–8.
Rodan GA. Mechanisms of action of bisphosphonates. Annu Rev Pharmacol Toxicol. 1998; 38: 375–88.
Lin JH, Duggan DE, Chen IW, et al. Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals. Drug Metab Dispos. 1991; 19(5): 926–32.
Sato M, Grasser W, Endo N, et al. Bisphosphonate action, alendronate localization in rat bone and effects on osteoclast. J Clin Invest. 1991; 88(6): 2095–105.
Masarachia P, Weinreb M, Balena R, et al. Comparison of the distribution of
H-etidronate in rat and mouse bones. Bone. 1996; 19(3): 281–90.
Zimolo Z, Wesolowski G, Rodan GA. Acid extrusion is induced by osteoclast attachment to bone. Inhibition by alendronate and calcitonin. J Clin Invest. 1995; 96(5): 2277–83.
Opas EE, Rutledge SJ, Golub E, et al. Alendronate inhibition of protein-tyrosine-phosphatase-megl. Biochem Pharmacol. 1997; 54: 721–7.
Schmidt A, Rutledge SJ, Endo N, et al. Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate. Proc Natl Acad Sci USA. 1996; 93: 3068–73.
Skorey K, Ly HD, Kelly J, et al. How does alendronate inhibit protein-tyrosine phosphatases? J Biol Chem 1997; 272(36): 22472–80.
Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA. 1999; 96: 133–8.
Luckman SP, Coxon FP, Ebetino FH, et al. Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure-activity relationships in J774 macrophages. J Bone Miner Res. 1998; 13(11): 1668–78.
Hughes DE, Wright KR, Uy HL, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res. 1995; 10: 1478–87.
Sahni M, Guenther HL, Fleisch H, et al. Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J Clin Invest. 1993; 91(5): 2004–11.
Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996; 18(2): 75–85.
Frith JC, Monkkonen J, Blackburn GM, et al. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(βγ-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res. 1997; 12(9): 1358–67.
Lin JH, Chen I-W, deLuna FA. On the absorption of alendronate in rats. J Pharm Sci. 1994; 83: 1741–6.
Lin JH, Chen I-W, deLuna FA. The role of calcium in plasma protein binding and renal handling of alendronate in hyperand hypocalcemie rats. J Pharmacol Exp Ther. 1993; 267: 670–5.
Lin JH, Chen I-W, deLuna FA. Effects of dose, sex, and age on the disposition of alendronate, a potent antiosteolytic bisphosphonate, in rats. Drug Metab Dispos. 1992; 20: 473–8.
Lin JH, Chen I-W, deLuna FA. Renal handling of alendronate in rats: an uncharacterized renal transport system. Drug Metab Dispos. 1992; 20: 608–13.
Kline WF, Matuszewski BK. Improved determination of the bisphosphonate alendronate in human plasma and urine by automated precolumn derivatization and high performance liquid chromatography with fluorescence and electrochemical detection. J Chromatogr. 1992; 583: 183–93.
Data on file, Merck Research Laboratories.
Cocquyt V, Kline SF, Gertz BJ, et al. Pharmacokinetics of intravenous alendronate. J Clin Pharmacol 1999 Apr; 39(4): 385–93.
Khan SA, Kanis JA, Vasikaran S, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 1997; 12(10): 1700–7.
Gertz BJ, Holland SD, Kline WF, et al. Studies of the oral bioavailability of alendronate. Clin Pharm Ther. 1995; 58(3): 288–98.
Physician’s desk reference. 52nd ed. Montvale (NJ): Medical Economics Co., Inc. 1998: 1657–61.
De Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996; 335(14); 1016–21.
Dempster DW. Bone remodeling in osteoporosis. In: Riggs BL, Melton LJ, editors. Osteoporosis, etiology, diagnosis and management. 2nd ed. New York: Lippincott-Raven, 1995: 67–92.
Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med. 1998; 338(11): 736–46.
Harris ET, Gertz BJ, Genant HK, et al. The effect 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(6): 1399–403.
Garnero P, Delmas PD. New developments in biochemical markers of osteoporosis. Calcif Tissue Int. 1996; 59 Suppl. 1: S2–9.
Garnero P, Shih WJ, Gineyts E, et al. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 1994; 79: 1693–700.
Siris ES. Clinical review: Paget’s disease of bone. J Bone Miner Res. 1998; 13(7): 1061–5.
PubMed CrossRef Copyright information
© Adis International Limited 1999