Forosa Mechanism of Action

Pharmacotherapeutic group: Drugs for treatment of bone diseases, drugs affecting bone structure and mineralisation, bisphosphonates. ATC code: M05BA04.
Pharmacology: Pharmacodynamics: The active substance in sodium alendronate trihydrate is a bisphosphonate that inhibits osteoclastic bone resorption without any direct effect on bone formation. Preclinical studies have demonstrated a preference for localisation of alendronate to sites where active resorption takes place. Osteoclastic activity is inhibited, but formation and binding of the osteoclasts is not affected. Bone formed during treatment with alendronate is of normal quality.
Treatment of post-menopausal osteoporosis: Osteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 standard deviations below the mean value of a normal young population or as a previous fragility fracture, irrespective of bone mineral density.
The effects of alendronate on BMD and fracture incidence in post-menopausal women were studied in two initial efficacy studies of identical design (n=994), and in the Fracture Intervention Trial (FIT: n=6,459).
In the initial efficacy studies, the increases in BMD with alendronate 10 mg daily relative to placebo after three years were 8.8%, 5.9% and 7.8% at the spine, femoral neck and trochanter, respectively. Total BMD also increased significantly. In the patients treated with alendronate, the proportion of patients who suffered one or more vertebral fractures was reduced by 48% (alendronate 3.2% versus placebo 6.2%). In the two-year extensions of these studies, the BMD in the spine and trochanter continued to increase. In addition, BMD at the femoral neck and total body was maintained.
The FIT study included two placebo-controlled trials in which alendronate was given daily (5 mg daily for two years and 10 mg daily for a further one or two years).
FIT 1: A three-year study with 2,027 patients who had 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% versus placebo 15.0%). In addition, a statistically significant reduction in the incidence of hip fractures was confirmed (1.1% versus 2.2%, a reduction of 51%).
FIT 2: A four-year study with 4,432 patients who had a low bone mass but had not had any vertebral fracture at the start of the study. In this study, in a subgroup analysis of osteoporotic women (37% of the total population who fulfilled the definition of osteoporosis given as previously mentioned), a significant difference was seen in the incidence of hip fractures (alendronate 1.0% versus placebo 2.2%, a reduction of 56%) and in the incidence of ≥1 vertebral fracture (2.9% versus 5.8%, a reduction of 50%).
The therapeutic equivalence of alendronate once-weekly tablets (n=519) and alendronate 10 mg daily (n=370) was demonstrated in a one-year multicentre study in post-menopausal women with osteoporosis. The mean increases from baseline of BMD in the lumbar spine after one year was 5.1% (95% confidence interval: 4.8, 5.4%) in the group receiving 70 mg once per week and 5.4% (95% confidence interval: 5.0, 5.8%) in the group receiving 10 mg daily. The average increases in BMD in the group receiving 70 mg once per week and in the group receiving 10 mg daily were 2.3% and 2.9% in the femoral neck and 2.9% and 3.1% over the total hip. The two treatment groups were also similar with regard to increased bone density in other parts of the skeleton.
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: Compared with an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg given after an overnight fast and two hours before a standardised breakfast. Bioavailability decreased to an estimated 0.46% and 0.39% when alendronate was given an hour or half an hour before a standardised breakfast.
In osteoporosis studies, alendronate was effective when it was given at least 30 minutes before the first meal or drink of the day.
Bioavailability was negligible irrespective of whether alendronate was given together with or up to two hours after a standardised breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approx. 60%. In healthy persons, oral prednisolone (20 mg three times daily for five days) did not result in any clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20% to 44%).
Distribution: Studies in rats show that alendronate is initially distributed to soft tissues after intravenous administration of 1 mg/kg, but is then rapidly redistributed to the skeleton or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of active substance 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 alendronate is metabolised in animals or humans.
Elimination: Following a single intravenous dose of (¹⁴C) alendronate, 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 intravenous dose of 10 mg, the renal clearance of alendronate was 71 mL/min and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not thought to interfere with the excretion of other active substances by those systems in humans.
Characteristics in patients: Preclinical studies show that the active substance 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 alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function (see Dosage & Administration).
Toxicology: Preclinical safety data: Non-clinical 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 fetal ossification. The relevance to humans is unknown.