Alendra Mechanism of Action

Pharmacology: Pharmacodynamics: Alendronate is a bisphosphonate whose main action is to inhibit osteoclast-mediated bone resorption.
Alendronate binds preferentially to active sites of bone resorption where it inhibits the resorptive activity of osteoclasts without inhibiting osteoblast function. Alendronate decreases bone turnover by inhibiting osteoclast action which results in a progressive increase in bone mass and subsequent decrease in osteoporosis-related fractures.
By inhibiting bone resorption, alendronate decreases the concentration of substances released from the bone and leads to significant reductions in plasma calcium and phosphate. This effect may be valuable in severe hypercalcemia, such as that associated with malignancy.
Pharmacokinetics: Alendronate's oral bioavailability is very low and estimated to be about 0.64% in women for doses ranging from 5 to 70 mg and 0.59% in men for 10 mg doses when administered after an overnight fast and two hours before a standardized breakfast.
Food decreases alendronate's bioavailability by about 85-90% while coffee or orange juice reduces absorption by 60%. Taking other medications, especially any calcium-containing compound and multivalent cations, will bind the bisphosphonate and thus also reduce alendronate's absorption. On the other hand, elevation of gastric pH to above 6 will result in a two-fold increase in alendronate absorption. About 60-70% of alendronate absorption occurs within one hour after oral administration.
Alendronate is transiently distributed to soft tissues after absorption. About 60% of the systemic dose is then rapidly redistributed to the bone and 40% is excreted by the kidney.
Alendronate is about 78% bound to plasma protein at pH 7.4, 2.5 mmol/L calcium, and 1 mg/L alendronate concentration. Plasma protein binding is increased with decreasing alendronate concentration and increasing pH and calcium.
Alendronate does not undergo metabolism. After oral administration, about 40% of the absorbed dose is excreted in the urine unchanged within 8 hours then the next 5% of the dose is excreted over the next 64 hours. Renal clearance is comparable to the glomerular filtration rate. Alendronate's biliary elimination is negligible with less than 2% of the administered dose appearing in the feces.
Alendronate's rate of clearance to bone is comparable to that of plasma flow through this tissue and its mean terminal half-life is estimated to exceed 10 years reflecting the amount of alendronate released from the skeleton. Therefore, it is estimated that after 10 years of oral treatment with alendronate 10 mg daily, the amount of alendronate released daily from the skeleton is approximately 25% of the amount absorbed from the gastrointestinal tract.