This study showed that risedronate 150-mg once a month provides similar efficacy and safety at 2 years compared with risedronate 5-mg daily for the treatment of postmenopausal osteoporosis. This adds to the range of risedronate dosing options and provides an alternative for patients who prefer once-a-month dosing. Risedronate is effective in the treatment of postmenopausal osteoporosis in oral daily, weekly, or on two consecutive days per month doses. This 2-year randomized, double-blind, multicenter study assesses the efficacy and safety of a single risedronate 150-mg once-a-month oral dose compared with the 5-mg daily regimen. Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5-mg daily (n = 642) or 150-mg once a month (n = 650) for 2 years. Bone mineral density (BMD), bone turnover markers, new vertebral fractures, and adverse events were evaluated. The primary efficacy endpoint was the mean percent change from baseline in lumbar spine BMD after 1 year. Four hundred ninety-eight subjects in the daily group (77.6 %) and 513 subjects in the once-a-month group (78.9 %) completed the study. After 24 months, the mean percent change in lumbar spine BMD was 3.9 % (95 % confidence interval [CI], 3.43 to 4.42 %) and 4.2 % (95 % CI, 3.68 to 4.65 %) in the daily and once-a-month groups, respectively. The once-a-month regimen was determined to be non-inferior to the daily regimen. The mean percent changes in BMD at the hip were similar in both dose groups, as were changes in biochemical markers of bone turnover. The incidence of adverse events, adverse events leading to withdrawal, and upper gastrointestinal tract adverse events were similar in the two treatment groups. After 2 years, treatment with risedronate 150-mg once a month provided similar efficacy and tolerability to daily dosing and provides an alternative for patients who prefer once-a-month oral dosing.

Long-term use of high-dose corticosteroids often results in bone loss, which may lead to osteoporosis-related fractures. This was a multicenter, double-blind study in which 290 ambulatory men and women receiving high-dose oral corticosteroid therapy (prednisone > or = 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12. Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures. Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010). Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group. Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events. We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients with corticosteroid-induced osteoporosis.

AIMS:To determine the relationship between risedronate pharmacokinetics and renal function. METHODS:Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS:Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS:Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).

Risedronate is a pyridinyl bisphosphonate approved for the treatment of Paget's disease (US‐FDA) and in development for the treatment and prevention of osteoporosis. This study examined risedronate pharmacokinetics and tolerability after oral administration using a randomized, double‐blind, parallel‐group design. Healthy male and female volunteers (n = 22–23 subjects per dose) received a single oral dose of 2.5, 5, or 30 mg risedronate. Serum and urine samples were collected for 72 and 672 hours, respectively, and risedronate concentrations were determined by ELISA. Safety was evaluated by monitoring adverse events, clinical laboratory measurements, vital signs, and electrocardiograms. Mean Cmax (0.41, 0.94, and 5.1 ng/mL for 2.5, 5, and 30 mg, respectively), AUC (1.8, 3.9, and 21 ng•h/mL for 2.5, 5, and 30 mg, respectively), and urinary excretion (22, 63, and 260 μg for 2.5, 5, and 30 mg, respectively) were dose proportional, and there were no significant differences in tmax or CLR among the three doses. All doses were well tolerated; no serious adverse events occurred, and all but one of the adverse events were mild or moderate in severity. There was no evidence of an acute phase reaction occurring after oral administration of risedronate.

Thirteen patients with severe Paget’s disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.

Risedronate monosodium [1-hydroxy-2-(3-pyridinyl)ethylidene bisphosphonic acid monosodium salt] is a pyridinyl bisphosphonate drug under development as a treatment for Paget's disease of bone and other metabolic bone disorders. An open-label, single-center study was conducted to determine the efficacy and safety of oral resedronate in patients with severe Paget's disease [mean baseline serum alkaline phosphatase (ALP) about six times the upper limit of normal]. 20 patients (12 men, 8 women; mean age 74 years) were treated with 30 mg/day of oral risedronate for 84 days, followed by 112 days without treatment. This 196 day period was repeated once in 19 patients in whom ALP did not reach the midpoint of the normal range or increased by > or = 25% from the nadir value by the end of the first 196 day period. At the end of the first 196 day period, the mean percentage decrease from baseline in excess ALP and excess urinary hydroxyproline/creatinine (OHP/Cr) was 79.5% and 85.5%, respectively (excess defined as difference between the patient's ALP or OHP/Cr and midpoint of the normal range). At the end of the second period, the decreases were 86.3% and 101.3%, respectively. The decreases in excess ALP and OHP/Cr were significant (p < 0.0001). In 13 patients (65%), ALP normalized: 8 during the first treatment period and 5 during the second. There was a progressive decline and elimination of pagetic bone pain: 70% (14 of 20) of patients reported pagetic bone pain at baseline, 25% (5 of 20) reported pain after the first 196 day period; and 0% at retreatment day 56 (p = 0.003). Thereafter, all patients remained pain-free until the end of the study. No patients withdrew from the study due to adverse events, and no adverse events were judged related to the study drug. In summary, 30 mg/day of oral risedronate given in 3 month course significantly reduced the biochemical indices of disease activity, showing normalization of ALP in the majority of patients with severe Paget's disease, and was associated with a significant reduction in pagetic bone pain. Risedronate was well-tolerated and demonstrated a good safety profile.

An open‐label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196‐day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by ≥25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant ( p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 ( p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.