Alendronate

Abstract

Alendronate is an aminobisphosphonate which appears to attenuate, rather than completely inhibiting bone turnover, by suppressing the activity of osteoclasts. Clinical trials have established that 10 mg/day orally administered alendronate is the optimum dosage. Despite its poor bioavailability after oral administration, alendronate is highly effective at preventing bone loss associated with the absence of endogenous estrogen. A sustained increase in bone mass was observed during alendronate therapy without accelerated loss after withdrawal of the drug. Increased bone mass was associated with a reduction in the risk and rate of occurrence of vertebral fractures. A recent study demonstrated a 47% reduction in the risk of developing new radiographic vertebral fractures over 3 years in women with low bone mass and pre-existing vertebral fractures. There have been few direct comparisons in clinical trials. However, when compared with calcium or low dosages of salmon calcitonin (salcatonin) therapy in women with postmenopausal osteoporosis, alendronate induced a sustained increase in bone mass during therapy that was not seen with the comparator. In clinical trials alendronate was generally well tolerated when taken as recommended. Adverse events tended to be transient and usually associated with the upper gastrointestinal tract; the most common events included abdominal pain, nausea, dyspepsia, constipation and diarrhoea, which are also common with other bisphosphonates. Of potential concern are the small number of reports of patients developing oesophageal ulcération; however, this adverse event was attributed to noncompliance with the manufacturer’s recommendations for administration of the drug. In addition, alendronate has not been associated with osteomalacia. Studies are still required to establish the long term efficacy of alendronate, particularly with regard to other available therapies. Although estrogen replacement therapy is generally considered the treatment of choice for the management of postmenopausal osteoporosis, many women are unable or unwilling to receive estrogens on a long term basis. Thus, alendronate, with its demonstrated beneficial effects and its good tolerability profile (when taken as recommended), is a promising alternative treatment option for the management of postmenopausal osteoporosis. Animal studies have indicated that at concentrations which elicit a physiological response, alendronate adsorbs to exposed bone surfaces and prevents the resorptive activity of osteoclasts without injuring them. Alendronate increases bone strength in ovariectomised rats but the effect on bone stiffness is inconclusive. Nevertheless, the potential effects of alendronate on bone metabolism in the absence of estrogen have been demonstrated. In postmenopausal women, biochemical markers of bone resorption were dose-dependently decreased 3 weeks after the initiation of alendronate (5 to 40 mg/day) and were reduced by at least 47% after 3 months. Similar decreases in markers of bone formation were observed 6 to 9 months after initiation of therapy. The depressed levels of all markers were maintained for the duration of therapy. Alendronate attenuated the increased level of bone turnover observed in postmenopausal women to within 1 standard deviation of that observed in premenopausal women. In preclinical trials, alendronate showed a marked, dose-dependent efficacy in preventing osteoporosis related to non—weight bearing and immobilisation. The bioavailability of alendronate after oral administration is less than 1% and is reduced by the presence of food and divalent ions, such as calcium, in the stomach; an increase in gastric pH effects an increase in bioavailability. Alendronate is rapidly distributed from plasma; over 95% is cleared 6 hours after intravenous infusion, with the remainder being undetectable after a further 6 hours. Elimination of alendronate appears to be exclusively via the urine in a multiphasic manner. Clinical studies have estimated a 10-year elimination half-life, suggesting a prolonged sequestration of the drug within bone tissue. Alendronate has a high specific affinity for actively metabolising bone tissue, and to date, no metabolites have been identified. The latter may be a reflection of the stability of the drug. In several large clinical studies in postmenopausal women with osteoporosis, alendronate (usually 5 to 20 mg/day) increased bone mineral density (BMD); effects were sustained over a period of 2 to 3 years during continued administration of the drug and for up to 12 months after discontinuation of treatment. For example, alendronate 10 mg/day for 3 years increased BMD in the lumbar spine 6.8 to 9.6% compared with decreases of approximately 0.7% noted in placebo recipients. There is evidence that both cortical and trabecular bone tissue are affected, suggesting that observed total bone mass increases of up to 1.6% with alendronate 10 mg/day were not merely the result of bone mineral redistribution. In studies that monitored fracture rate, daily administration of alendronate 5 to 20mg compared with placebo prevented the rate of development of new vertebral fractures. A consistent but nonsignificant dose-related decrease in the risk of fractures was observed which was independent of age and the presence of existing fractures. Alendronate also reduced the severity of fractures which occurred. Pooled data from 5 studies of 2 to 3 years’ duration indicate that the relative risk rate and cumulative proportion of non-vertebral fractures were linear over time with placebo, but reduced in alendronate recipients. In addition, results from the Fracture Intervention Trial demonstrated a significant 47% decrease in the risk of developing new radiographic vertebral fractures in postmenopausel women with low bone mass and pre-existing vertebral fractures who received alendronate for 3 years compared with placebo recipients. There...