Risedronate

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Abstract
Risedronate is a novel orally administered pyridinyl bisphosphonate indicated for the prevention or treatment of postmenopausal and glucocorticoid-induced osteoporosis and Paget’s disease. The drug reduces bone turnover and decreases resorption chiefly through osteoclastic effects, with no undesirable effects on cortical porosity or thickness or on cancellous bone volume. Four randomised, double-blind trials have been carried out in 4873 patients with postmenopausal osteoporosis. In 2 of these studies, the primary end-point of vertebral fracture incidence was reduced by risedronate 5mg once daily by up to 65 and 49% relative to placebo after 1 and 3 years, respectively. Across all 4 trials, risedronate improved lumbar spine, femoral neck and femoral trochanter bone mineral density (BMD) statistically significantly relative to placebo. The drug also prevented bone loss in a study in 383 women with recent menopause, and reduced the risk of hip fracture in elderly women with confirmed osteoporosis in a trial involving a total of 9331 patients. Risedronate 5 mg/day plus estrogen has been shown to be superior to estrogen alone in a 12-month double-blind study in 524 women with at least 1-year’s history of menopause. Two randomised, double-blind and placebo-controlled 12-month studies in a total of 518 patients have shown risedronate 5 mg/day to prevent or reverse bone loss in patients receiving glucocorticoid therapy. Risedronate 30 mg/day was associated with statistically significant reductions in mean serum levels of alkaline phosphatase (ALP) in noncomparative studies in patients with Paget’s disease. ALP normalisation rates ranged from 53.8 to 65% across two 84-day treatment cycles in 2 of these trials in 180 patients. In a randomised, double-blind study in 123 patients, risedronate 30 mg/day for 2 months evoked significantly greater serum ALP responses than etidronate 400 mg/day for 6 months. The overall tolerability profile of risedronate was similar to that of placebo in clinical studies, with no evidence of acute-phase reactions or mineralisation defects, or excess incidence of upper GI lesions, in patients receiving the drug. Conclusions: Risedronate is an effective and well tolerated novel bisphosphonate that is suitable for first-line therapy in Paget’s disease. The rapid and sustained reductions in vertebral fracture incidence and BMD changes seen in patients with postmenopausal and glucocorticoid-induced osteoporosis indicate the drug to be a valuable treatment option with first-line potential, particularly in patients for whom hormonal therapy is inappropriate. The effects of the drug on hip fracture incidence in elderly women with confirmed osteoporosis point to a particular role in older patients, or those with more advanced disease. Risedronate inhibits bone resorption by interfering with the recruitment and activity of osteoclasts. As with other bisphosphonates, the drug is believed also to inhibit osteoclastic adhesion to mineralised bone matrix and to shorten the osteoclastic life span. Risedronate 5 mg/day (all dosages quoted are oral unless stated otherwise) reduces bone turnover as shown consistently in clinical studies in postmenopausal women and patients with Paget’s disease by statistically significant reductions relative to placebo in serum levels of bone-specific ALP. Maximal reductions are typically obtained after 6 months’ treatment and are accompanied by reductions in urinary markers of bone resorption (e.g. N-telopeptide and deoxypyridinoline). Histomorphometric analysis in patients receiving risedronate for corticosteroid-induced osteoporosis showed decreased resorption depth with unchanged rates of resorption (resulting in a net decrease in bone resorption) with the drug. There were no undesirable effects on cortical porosity or thickness or on cancellous bone volume. Trabecular width and rates of mineralisation remained unchanged, and bone turnover decreased, in patients with skeletal deterioration caused by multiple myeloma who received risedronate. Risedronate undergoes rapid absorption and shows a dose-proportional pharmacokinetic profile after oral administration. Mean peak serum concentrations (Cmax) of risedronate were 0.41, 0.94 and 5.1 μg/L after single doses of 1.5, 5 and 30mg, respectively, in healthy volunteers. Mean times to Cmaxranged from 0.81 to 0.87 hours. GI absorption of the drug is impaired by the presence of food, and by calcium-, magnesium- or aluminium-containing compounds. The volume of distribution at steady state of risedronate was 6.3 L/kg after intravenous administration in 1 study. The terminal elimination half-life is long (480 hours), and the drug is excreted unchanged largely via the kidneys, with renal clearance (CLR) accounting for 87% of total clearance. CLR and volume of distribution are related linearly to creatinine clearance (CLCR). Risedronate is known not to interfere with the function of hepatic microsomal cytochrome P450 enzymes. Postmenopausal Osteoporosis. Following the demonstration of efficacy relative to placebo of risedronate in women with postmenopausal osteoporosis in phase II studies, the drug was compared with placebo in a series of 6 randomised, double-blind phase III clinical trials. Four of these studies involved risedronate treatment of 4873 patients with low bone mass; vertebral fracture incidence was measured as the primary end-point in 2 of these, which involved women with established osteoporosis at baseline. The other studies focused on prevention of osteoporosis (i.e. maintenance of baseline bone mass) in women with recent menopause, and reduction of risk of hip fracture in elderly women. Statistically significant improvements relative to placebo in vertebral fracture incidence and/or in lumbar spine, femoral neck and femoral trochanter BMD were seen consistently with risedronate 5mg once daily. In...