Drugs

, Volume 61, Issue 5, pp 685–712

Risedronate

A Review of its Pharmacological Properties and Clinical Use in Resorptive Bone Disease
Adis Drug Evaluation

DOI: 10.2165/00003495-200161050-00013

Cite this article as:
Dunn, C.J. & Goa, K.L. Drugs (2001) 61: 685. doi:10.2165/00003495-200161050-00013

Summary

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.

Pharmacological Profile

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.

Therapeutic Use

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 the 2 vertebral fracture studies, significant (61 and 65%; p ≤ 0.001 vs placebo) reductions in vertebral fracture risk were evident with risedronate treatment by the end of the first year. The risk of new fractures was reduced over 3 years by 41 (p = 0.003) and 49% (p < 0.001) relative to placebo. There were also substantial (39 and 33%) reductions in the risk of nonvertebral fracture (the first of these 2 results was also statistically significant).

Statistically significant improvements relative to placebo in BMD were noted from 6 months onwards with risedronate 5 mg/day in the vertebral fracture studies. After 3 years, mean treatment differences of 5.9, 6.4, 3.1 and 2.1% were reported for the lumbar spine, femoral trochanter, femoral neck and midshaft radius, respectively (all p < 0.001 vs placebo), in 1 trial.

In the 2 studies in patients with low baseline bone mass in which BMD was the primary end-point, mean lumbar spine BMD increased from baseline by 4.1% over 2 years (p < 0.001 vs placebo) in 1 trial and by 4.7% over 18 months (p < 0.05 vs placebo) in the other with risedronate 5 mg/day.

Statistically significant increases relative to both baseline and placebo with risedronate 5 mg/day in spinal and hip BMD were reported from as early as 3 months after starting treatment in a preliminary report of the bone loss prevention study in 383 women with a history of recent (6 to 36 months) menopause.

Risedronate treatment reduced the risk of the primary end-point of hip fracture in elderly women with established osteoporosis as confirmed by low BMD in a 3-year study in which 9331 patients were randomised within 2 strata to risedronate 2.5 or 5mg daily or placebo. In group 1 (patients aged 70 to 79 years with confirmed osteoporosis at baseline), hip fracture incidences were 1.9% with risedronate and 3.2% with placebo (relative risk 0.6; p = 0.009). The relative risk of hip fracture associated with risedronate treatment in 1703 women in group 1 with evidence of at least 1 vertebral fracture at baseline was 0.4 (p = 0.003 vs placebo). The corresponding relative risk in 2648 group 1 women with no history of vertebral fracture was 0.6 (p = 0.14).

There was no significant effect of risedronate treatment on hip fracture risk in group 2 (patients aged 80 years and over, most of whom were recruited on the basis of presence of clinical risk factors only): hip fracture incidences of 4.2 and 5.1% were reported for the risedronate and placebo groups, respectively (p = 0.35). Further analysis suggested that the majority of patients in group 2 did not have osteoporosis. Overall, incidences of hip fracture were 2.8% in all women who received risedronate and 3.9% in those who received placebo in this study (relative risk 0.7; p = 0.02).

BMD measurements indicated superiority of risedronate 5 mg/day plus estrogen therapy (n = 261) over estrogen alone (n = 263) in a 12-month double-blind placebo-controlled study in women with at least 1 year’s history of menopause. Improvements with risedronate plus estrogen were significantly greater than those with estrogen alone at 6 months for the lumbar spine and at 12 months for the femoral neck and midshaft radius.

Glucocorticoid-Induced Osteoporosis. In a randomised, double-blind, placebo-controlled phase III study in 228 patients starting glucocorticoid therapy, lumbar spine, femoral neck and femoral trochanter BMD decreased from baseline by around 3% over 12 months in patients receiving placebo. In contrast, BMD was maintained at the lumbar spine and femoral neck, and was increased at the femoral trochanter, with risedronate 5 mg/day. Least squares mean differences from placebo were 3.8, 4.1 and 4.6%, respectively (all p < 0.001). BMD was also maintained in recipients of risedronate 2.5 mg/day, but effects were less marked than with the 5 mg/day dosage. Distal and midshaft radius BMD did not change significantly relative to baseline in any group, and there were no statistically significant differences from placebo with either active treatment.

Risedronate 5 mg/day significantly increased BMD relative to placebo at the lumbar spine and the femoral neck and trochanter in 290 patients on glucocorticoid therapy and with low BMD at baseline in another 12-month randomised double-blind study.

Although neither trial was designed to detect differences between treatment groups with respect to incidence of vertebral fracture, combined results from the 2 studies nevertheless indicated an encouraging overall 70% reduction in this end-point (p = 0.01 vs placebo).

Paget’s Disease. In 2 noncomparative studies in which risedronate 30mg was given once daily for 84 days (with additional 112-day follow-up) in 20 and 160 patients with moderate to severe Paget’s disease, mean serum ALP levels were reduced from the first post-baseline measurement (day 29) onwards (p < 0.001 vs baseline for both studies). Patients whose serum ALP levels did not normalise received a second cycle of treatment; ALP normalisation rates were 65 and 53.8% across both cycles in these 2 studies. All patients were free from pain by day 56 of the second cycle in the smaller study; in the larger trial, 42% of 154 evaluable patients were pain-free on day 196 (p < 0.001 vs baseline).

Risedronate 30mg once daily for 2 months has been compared with etidronate 400mg daily for 6 months in 123 patients with Paget’s disease in a randomised double-blind trial with 12- and 18-month follow-up. Both drugs were associated with reductions from baseline (p < 0.01) in serum levels of ALP from 1 month onwards, but risedronate evoked greater responses than etidronate (p < 0.001 between treatments). Maximum mean changes from baseline in ALP were seen at 6 months and were 69 and 33% for risedronate and etidronate, respectively. Biochemical remission was achieved in 77 and 11% of patients by month 6 (p < 0.001). After 18 months, 53 and 14% of evaluable risedronate and etidronate recipients, respectively, had serum ALP levels within the normal range. There was no statistically significant difference between treatments in mean pain scores, and no significant improvements in other quality-of-life measures (Short Form Health Survey) were reported with either drug.

Tolerability

Adverse event reporting rates were 92.1% with risedronate 5mg daily and 92.8% with placebo in patients below 80 years of age in an analysis of tolerability results from 10 068 individuals included in an assessment of 15 066 patients enrolled in placebo-controlled clinical studies. Corresponding rates in patients aged 80 years and over were 87.9 and 88.3%. Withdrawal rates were also similar between treatment groups for both age categories.

According to collated data from over 5700 patients in phase III osteoporosis studies, overall incidences of serious adverse events were 24.9% with placebo and 26.3% with risedronate 5 mg/day; rates of withdrawal from treatment were 14.4 and 13.5%, respectively. Risedronate 10 to 30 mg/day was well tolerated by 392 patients with Paget’s disease who participated in clinical trials. Similar tolerability profiles between treatment groups were apparent in a clinical trial comparing risedronate 30 mg/day with etidronate 400 mg/day, with the most commonly reported adverse events possibly or probably related to study medication (both drugs) being arthralgia, diarrhoea, headache, abdominal pain and skin rash.

Tolerability data from the analysis of 15 066 patients randomised in clinical studies to risedronate or placebo treatment have shown no excess incidence relative to placebo of upper GI lesions in patients receiving risedronate 5 mg/day. Similarity between groups was maintained in patients with a history of upper GI disease, those receiving NSAID or aspirin treatment, and those using histamine H2-receptor antagonists or proton pump inhibitors.

Rates of gastric ulceration after endoscopic examination on days 8 and 15 in a recent 2-week study in 448 healthy postmenopausal women were 4.1% with risedronate 5 mg/day and 13.2% with alendronate 10 mg/day (p < 0.001). Another study in 235 patients has shown similar mean gastric erosion scores after 28 days’ therapy with risedronate 30 mg/day or alendronate 40 mg/day. There have been no reports of any acute-phase reactions, age-related increases in adverse event reporting or mineralisation defects in patients receiving risedronate therapy.

Dosage and Administration

Risedronate tablets should be taken once daily at least 30 minutes before the first meal or drink (other than water) of the day, and should be swallowed with a full glass of water by patients in an upright position. Patients should not lie down for at least 30 minutes after taking risedronate. Supplemental calcium and calciferol should be prescribed for those whose dietary intake is inadequate.

The recommended daily dosage of risedronate for the prevention or treatment of postmenopausal and glucocorticoid-induced osteoporosis is 5mg. Patients with Paget’s disease should receive 30mg daily for 2 months, with a second course after an additional 2-month treatment-free observation period if serum ALP levels do not normalise or disease relapse is seen.

There are no data on the use of risedronate in pregnant or nursing women. No dosage adjustment is necessary in elderly patients or in those with mild to moderate renal impairment (CLCR≥1.8 L/h). The drug is not recommended in patients with CLCR below 1.8 L/h, however.

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand