Weekly administration of alendronate: Rationale and plan for clinical assessment

Objective: This paper describes the rationale and supporting data for once- weekly dosing of alendronate. Background: Alendronate sodium, a bisphosphonate that potently inhibits bon e resorption, has been shown to increase bone mass and substantially reduce the incidence of osteoporotic fractures, including fractures of the hip. T he standard regimen of daily administration has generally been well tolerat ed. However, weekly administration may provide greater convenience to patie nts 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 resorptio n in individual remodeling units normally proceeds for similar to 2 weeks; alendronate inhibits the rate and extent of resorption. Because the half-li fe 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 s trength. Animal studies demonstrate that both weekly and daily parenteral a dministration of alendronate effectively increase bone mass and strength, b ut confirmation of efficacy is needed for weekly oral dosing in humans. Alt hough daily bisphosphonates (alendronate and risedronate) elicited esophage al irritation in a canine model of gastroesophageal reflux, weekly dosing w ith 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 uppe r 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 an currently bei ng performed to assess the comparability of weekly, biweekly, and daily dos ing of alendronate with regard to effects on bone density, safety, and tole rability.