Pharmacotherapeutic Group: Bisphosphonates. ATC Code: M05BA07.
Pharmacology: Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. The bone turnover is reduced while the osteoblast activity and bone mineralisation are preserved. In preclinical studies, risedronate sodium demonstrated potent anti-osteoclast and antiresorptive activity, and dose dependently increased bone mass and biomechanical skeletal strength. The activity of risedronate sodium was confirmed by measuring biochemical markers for bone turnover during pharmacodynamic and clinical studies. In studies of postmenopausal women, decreases in the biochemical markers of bone turnover were observed within 1 month and reached a maximum in 3-6 months. Decreases in biochemical markers of bone turnover were similar with Actonel 35 mg once a week at 12 months.
In a study in men with osteoporosis, decreases in biochemical markers of bone turnover were observed at the earliest time point of 3 months and continued to be observed at 24 months.
Treatment of Postmenopausal Osteoporosis: A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density (BMD), early menopause, history of smoking and family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors.
Based on effects on mean change in lumbar spine BMD, Actonel 35 mg once a week (n=485) was shown to be equivalent to Actonel 5 mg daily (n=480) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis.
The clinical programme for risedronate sodium administered once daily studied the effect of risedronate sodium on the risk of hip and vertebral fractures and contained early and late postmenopausal women with and without fracture. Daily doses of 2.5 and 5 mg were studied and all groups, including the control groups, received calcium and vitamin D (if baseline levels were low). The absolute and relative risk of new vertebral and hip fractures were estimated by use of a time-to-first-event analysis.
In a double-blind, active-controlled, multicenter study of postmenopausal women with osteoporosis, 1 year of treatment with Actonel 150 mg once a month (n=650) was shown to be non-inferior to Actonel 5 mg daily (n=642). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 3.4% (3, 3.8; 95% CI) in the 5 mg daily group (n=561) and 3.5% (3.1, 3.9; 95% CI) in the 150 mg once a month group (n=561) with a mean difference between groups being -0.1% (-0.5, 2; 95% CI). The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. The number of patients with new vertebral fractures at month 12 and endpoint were similar in the 150 mg once a month group and the 5 mg daily group (at endpoint, 150 mg 1.4%; 5 mg daily 1.4%).
Two placebo-controlled trials (n=3661) enrolled postmenopausal women <85 years with vertebral fractures at baseline. Risedronate sodium 5 mg daily given for 3 years reduced the risk of new vertebral fractures relative to the control group. In women with respectively at least 2 or at least 1 vertebral fractures, the relative risk reduction was 49% and 41%, respectively (incidence of new vertebral fractures with risedronate sodium 18.1% and 11.3%, with placebo 29% and 16.3%, respectively). The effect of treatment was seen as early as the end of the 1st year of treatment. Benefits were also demonstrated in women with multiple fractures at baseline. Risedronate sodium 5 mg daily also reduced the yearly height loss compared to the control group.
Two further placebo-controlled trials enrolled postmenopausal women >70 years with or without vertebral fractures at baseline. Women 70-79 years were enrolled with femoral neck BMD T-score less than -3 SD (manufacturer's range ie, -2.5 SD using NHANES III) and at least 1 additional risk factor. Women ≥80 years could be enrolled on the basis of at least 1 nonskeletal risk factor for hip fracture or low BMD at the femoral neck. Statistical significance of the efficacy of risedronate versus placebo is only reached when 2 treatment groups 2.5 and 5 mg are pooled. The following results are only based on a-posteriori analysis of subgroups defined by clinical practice and current definitions of osteoporosis: In the subgroup of patients with femoral neck BMD T-score -2.5 SD or less (NHANES III) and at least 1 vertebral fracture at baseline, risedronate sodium given for 3 years reduced the risk of hip fractures by 46% relative to the control group (incidence of hip fractures in combined risedronate sodium 2.5 and 5 mg groups 3.8%, placebo 7.4%).
Data suggest that a more limited protection than this may be observed in the very elderly (≥80 years). This may be due to the increasing importance of nonskeletal factors for hip fracture with increasing age.
In these trials, data analysed as a secondary endpoint indicated a decrease in the risk of new vertebral fractures in patients with low femoral BMD without vertebral fracture and in patients with low femoral neck BMD with or without vertebral fracture.
Risedronate sodium 5 mg daily given for 3 years increased BMD relative to control at the lumbar spine, femoral neck, trochanter and wrist and maintained bone density at the midshaft radius.
In a 1-year follow-up off therapy after 3 years treatment with risedronate sodium 5 mg daily, there was a rapid reversibility of the suppressing effect of risedronate sodium on bone turnover rate.
Bone biopsy samples from postmenopausal women treated with risedronate sodium 5 mg daily for 2-3 years, showed an expected moderate decrease in bone turnover. Bone formed during risedronate sodium treatment was of normal lamellar structure and bone mineralisation. These data together with the decreased incidence of osteoporosis-related fractures at vertebral sites in women with osteoporosis appear to indicate no detrimental effect on bone quality.
Endoscopic findings from a number of patients with a number of moderate to severe gastrointestinal complaints in both risedronate sodium and control patients indicated no evidence of treatment-related gastric, duodenal or oesophageal ulcers in either group, although duodenitis was uncommonly observed in the risedronate sodium group.
Treatment of Osteoporosis in Men: Risedronate sodium 35 mg once a week demonstrated efficacy in men with osteoporosis (age range 36-84 years) in a 2-year, double-blind, placebo-controlled study in 284 patients (risedronate sodium 35 mg, n=191). All patients received supplemental calcium and vitamin D.
Increases in BMD were observed as early as 6 months following initiation of risedronate sodium treatment. Risedronate sodium 35 mg once a week produced mean increases in BMD at the lumbar spine, femoral neck, trochanter and total hip compared to placebo after 2 years of treatment.
Antifracture efficacy was not demonstrated in this study.
The bone effect [BMD increase and bone turnover markers (BTM) decrease] of risedronate sodium is similar in males and females.
Pharmacokinetics: Absorption: Absorption after an oral dose is relatively rapid (tmax approximately 1 hr) and is independent of the dose over the range studied (single-dose study: 2.5-30 mg; multiple-dose studies: 2.5-5 mg daily and up to 50 mg weekly). Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is administered with food. Bioavailability was similar in men and women.
Distribution: The mean steady-state volume of distribution is 6.3 L/kg in humans. Plasma protein-binding is about 24%.
Metabolism: There is no evidence of systemic metabolism of risedronate sodium.
Elimination: Approximately ½ of the absorbed dose is excreted in urine within 24 hrs, and 85% of an IV dose is recovered in the urine after 28 days. Mean renal clearance is 105 mL/min and mean total clearance is 122 mL/min, with the difference probably attributed to clearance due to adsorption to bone. The renal clearance is not concentration-dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unadsorbed risedronate sodium is eliminated unchanged in faeces. After oral administration, the concentration-time profile shows 3 elimination phases with a terminal half-life of 480 hrs.
Special Populations: Elderly: No dosage adjustment is necessary.
Acetylsalicylic Acid/NSAID Users: Among regular acetylsalicylic acid or NSAID users (≥3 days per week), the incidence of upper gastrointestinal adverse events in risedronate sodium-treated patients was similar to that in control patients.
Toxicology: Preclinical Safety Data: In toxicological studies in rat and dog, dose-dependent liver toxic effects of risedronate sodium were seen, primarily as enzyme increases with histological changes in rat. The clinical relevance of these observations is unknown. Testicular toxicity occurred in rat and dog at exposures considered in excess of the human therapeutic exposure. Dose-related incidences of upper airway irritation were frequently noted in rodents. Similar effects have been seen with other bisphosphonates. Lower respiratory tract effects were also seen in long-term studies in rodents, although the clinical significance of these findings is unclear. In reproduction toxicity studies at exposures close to clinical exposure, ossification changes were seen in sternum and/or skull of foetuses from treated rats and hypocalcaemia and mortality in pregnant females allowed to deliver. There was no evidence of teratogenesis at 3.2 mg/kg/day in rat and 10 mg/kg/day in rabbit, although data are only available on a small number of rabbits. Maternal toxicity prevented testing of higher doses. Studies on genotoxicity and carcinogenicity did not show any particular risks for humans.