Alendronic Acid 70 mg, Calcium 500 mg, Cholecalciferol 250 IU Tablets

Alendronate Sodium — Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

Cholecalciferol — Vitamin D3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D3. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver. Conversion to the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption.

Alendronate Sodium — Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10-mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.

In a study, the alendronate in the FOSAMAX PLUS D (70 mg/2800 international units) tablet and the FOSAMAX (alendronate sodium) 70-mg tablet were found to be equally bioavailable. In a separate study, the alendronate in the FOSAMAX PLUS D (70 mg/5600 international units) tablet was found to be equally bioavailable to the alendronate in the FOSAMAX (alendronate sodium) 70-mg tablet.

A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.

Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

Cholecalciferol — Following administration of FOSAMAX PLUS D (70 mg/2800 international units) after an overnight fast and two hours before a standard meal, the baseline adjusted mean area under the serum-concentration-time curve (AUC0-120 hrs) for vitamin D3 was 120.7 ng-hr/mL. The baseline adjusted mean maximal serum concentration (Cmax) of vitamin D3 was 4.0 ng/mL, and the baseline adjusted mean time to maximal serum concentration (Tmax) was 10.6 hrs. The bioavailability of the 2800 international units vitamin D3 in FOSAMAX PLUS D is similar to 2800 international units vitamin D3 administered alone.

In a separate study, the baseline adjusted mean AUC0-80 hrs and baseline adjusted mean Cmax for vitamin D3 were 355.6 ng-hr/mL and 10.8 ng/mL, respectively. The baseline adjusted mean Tmax was 9.2 hrs. The bioavailability of the 5600 international units vitamin D3 in the FOSAMAX PLUS D is similar to 5600 international units vitamin D3 administered as two 2800 international units vitamin D3 tablets.

Alendronate Sodium — Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.

Cholecalciferol — Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.

Alendronate Sodium — There is no evidence that alendronate is metabolized in animals or humans.

Cholecalciferol — Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.

Calcium provides the mineral structure of bone and teeth. Ionized calcium also participates in muscle contraction, nerve signaling, blood coagulation and hormone secretion.

Intestinal uptake occurs by vitamin-D-dependent active transport and passive diffusion. The absorbed fraction depends on intake and formulation. Calcium carbonate is more dependent on gastric acid than calcium citrate. Most body calcium is held in the skeleton, which is continually remodeled and acts as a reservoir. These nutrient data do not establish this product's bioavailability.