No 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.

Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2.

Clinical studies were performed to examine the oral bioavailability of alendronate (4-amino-1-hydroxy-butylidene-1,1-bisphosphonate monosodium). All studies, with the exception of one performed in men, involved postmenopausal women. Short-term (24 to 36 hours) urinary recovery of alendronate after an intravenous dose of 125 to 250 micrograms averaged about 40% in both men and women. In women, oral bioavailability of alendronate was independent of dose (5 to 80 mg) and averaged (90% confidence interval) 0.76% (0.58, 0.98) when taken with water in the fasting state, followed by a meal 2 hours later. Bioavailability was similar in men [0.59%, (0.43, 0.81)]. Taking alendronate either 60 or 30 minutes before a standardized breakfast reduced bioavailability by 40% relative to the 2-hour wait. Taking alendronate either concurrently with or 2 hours after breakfast drastically (> 85%) impaired availability. Black coffee or orange juice alone, when taken with the drug, also reduced bioavailability (approximately 60%). Increasing gastric pH, by infusion of ranitidine, was associated with a doubling of alendronate bioavailability. A practical dosing recommendation, derived from these findings and reflective of the long-term nature of therapy for a disease such as osteoporosis, is that patients take the drug with water after an overnight fast and at least 30 minutes before any other food or beverage.

Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half-life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half-life of greater than 10 years (n ‫؍‬ 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1