Alendronate Sandoz Mechanism of Action

Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates. ATC code: M05BA04.
PHARMACOLOGY: Pharmacodynamics: Alendronate is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect on bone formation. Preclinical studies have shown preferential localisation of Aledronate to sites of active resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts is not affected. The bone formed during treatment with alendronic acid is of normal quality.
Treatment of post-menopausal osteoporosis: Osteoporosis is defined ad BMD of the spine or hip 2.5 SD below the mean value of a normal young population or as a previous fragility fracture, irrespective of BMD.
The therapeutic equivalence of Alendronate 70 mg (n=519) and Alendronate 10 mg daily (n=370) was demonstrated in a one-year multicentre study of post-menopausal women with osteoporosis. The mean increases from baseline in lumbar spine BMD at one year were 5.1%(95% CI: 4.8, 5.4%) in the 70 mg once-weekly group and 5.4%(95% CI:5.0, 5.8%) in the 10 mg daily group.
The effects of Alendronate on bone mass and fracture incidence in post-menopausal women were examined in two initial efficacy studies of identical design (n=994) as well as in the Fracture Intervention Trial (FIT: n=6,459).
In the initial efficacy studies, the mean bone mineral density (BMD) increses with Alendronate 10 mg/day relative to placebo at three years were 8.8%, 5.9% and 7.8% at the spine, femoral neck and trochanter, respectively. Total body BMD also increased significantly. There was a 48% reduction (Alendronate 3.2% vs placebo 6.2%) in the proportion of patients treated with Alendronate experiencing one or more vertebral fractures relative to those treated with placebo. In the two-year extension of these studies BMD at the spine and trochanter continued to increase and BMD at the femoral neck and total body were maintained.
FIT consisted of two placebo-controlled studies using Alendronate daily (5 mg daily for two years and 10 mg daily for either one or two additional years): FIT 1: A three-year study of 2,027 patients who had at least one baseline vertebral (compression) fracture. In this study Alendronate daily reduced the incidence of ≥1 new vertebral fracture by 47% (Alendronate 7.9% vs. placebo 15.0%). In addition, a statistically significant reduction was found in the incidence of hip fractures (1.1% vs. 2.2%, a reduction of 51%).
FIT 2: A four-year study of 4,432 patients with low bone mass but without a baseline vertebral fracture. In this study, a significant difference was observed in the analysis of the subgroup of osteoporotic woman (37% of the global population who correspond with the previously mentioned definition of osteoporosis) in the incidence of hip fractures (Alendronate 1.0% vs. placebo 2.2%, a reduction of 56%) and in the incidence of ≥1 vertebral fracture (2.9% vs. 5.8%, a reduction of 50%).
Paediatric patients: Alendronate sodium has been studied in a small number of patients with osteogenesis imperfecta under the age of 18 years. Results are insufficient to support the use of alendronate sodium in paediatric patients with osteogenesis imperfecta.
Pharmacokinetics: Absorption: Relative to an intravenous reference dose, the oral mean bioavailability of alendronic acid in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardised breakfast. Bioavailability was decreased similarly to an estimated 0.46% and 0.39% when alendronic acid was administered one hour or half an hour before a standardised breakfast. In osteoporosis studies, alendronic was effective when administered at least 30 minutes before first food or beverage of the day. Bioavailability was negligible whether alendronic acid was administered with, of up to two hours after, a standardised breakfast. Concomitant administration of alendronic acid with coffee or orange juice reduced bioavailability by approximately 60%.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in oral bioavailability of alendronic acid (a mean increase ranging from 20% to 44%).
Distribution: Studies in rats show that alendronic acid transiently distributes 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 litres in humans. Concentrations of drug in plasma following therapeutic oral doses are too low for analytical detection (<5 ng/ml). Protein binding in human plasma is approximately 78%.
Biotransformation: There is no evidence that alendronic acid is metabolised in animals or humans.
Elimination: Following a single intravenous dose of [14C] alendronic acid, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces. Following a single 10 mg intravenous dose, the renal clearance of alendronic acid was 71 ml/min, and systemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95% within six hours following intravenous administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronic acid from the skeleton. Alendronic acid is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other medicinal products by those systems in humans.
Characteristics in patients: Preclinical studies show that the drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after chronic dosing with cumulative intravenous doses up to 35 mg/kg in animals. Although no clinical information is available, it is likely that, as in animals, elimination of alendronic acid via the kidney will be reduced in patients with impaired renal function (see Dosage & Administration).
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in rats have shown that treatment with Alendronate during pregnancy was associated with dystocia in dams during parturition which was related to hypocalcaemia. In studies, rats given high doses showed an increased incidence of incomplete foetal ossification. The relevance to humans is unknown.