RISEDRONATE SODIUM 35 mg Film-coated tablet Ref.[7852] Active ingredients: Risedronic acid

Pharmacotherapeutic group: Bisphosphonates
ATC code: M05BA07

Mechanism of action

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 is preserved.

Pharmacodynamic effects

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 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 risedronate sodium 35 mg once weekly and risedronate sodium 5 mg daily at 12 months.

In a study in men with osteoporosis, decreases in biochemical markers of bone turnover were observed at the earliest timepoint of 3 months and continued to be observed at 24 months.

Clinical efficacy and safety

Treatment of Postmenopausal Osteoporosis

A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a 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, risedronate sodium 35 mg once weekly (n=485) was shown to be equivalent to risedronate sodium 5 mg daily (n=480) in a one-year, double-blind, multicentre 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 mg 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.

*Two placebo-controlled trials (n=3,661) enrolled postmenopausal women under 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 29.0% and 16.3%, respectively). The effect of treatment was seen as early as the end of the first 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 above 70 years with or without vertebral fractures at baseline. Women 70-79 years were enrolled with femoral neck BMD T-score < -3 SD (manufacturer’s range, i.e. -2.5 SD using NHANES III (National Health and Nutrition Examination Survey)) and at least one additional risk factor. Women ≥ 80 years could be enrolled on the basis of at least one non-skeletal risk factor for hip fracture or low bone mineral density at the femoral neck. Statistical significance of the efficacy of risedronate versus placebo is only reached when the two treatment groups 2.5 mg 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 (NHANES III) and at least one 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 mg 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 non-skeletal 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 neck 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 bone mineral density (BMD) relative to control at the lumbar spine, femoral neck, trochanter and wrist and maintained bone density at the mid-shaft radius.

In a one-year follow-up off therapy after three years treatment with risedronate sodium 5 mg daily there was 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 to 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 to 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 BTM decrease) of risedronate sodium is similar in males and females.

Paediatric population

The safety and efficacy of risedronate sodium has been investigated in a 3 year study (a randomized, double-blind, placebo-controlled, multicenter, parallel group study of one-year duration followed by 2 years of open-label treatment) in paediatric patients aged 4 to less than 16 years with mild to moderate osteogenesis imperfecta. In this study, patients weighing 10-30 kg received risedronate 2.5 mg daily and patients weighing more than 30 kg received risedronate 5 mg daily.

After completion of its one-year randomized, double-blind, placebo-controlled phase, a statistically significant increase in lumbar spine BMD in the risedronate group versus placebo group was demonstrated; however, an increased number of patients with at least 1 new morphometric (identified by x-ray) vertebral fracture was found in the risedronate group compared to placebo. During the one-year double-blind period, the percentage of patients who reported clinical fractures was 30.9% in the risedronate group and 49.0% in the placebo group.

In the open-label period when all patients received risedronate (month 12 to month 36), clinical fractures were reported by 65.3% of patients initially randomized to the placebo group and by 52.9% of patients initially randomized to the risedronate group. Overall, results are insufficient to support the use of risedronate sodium in paediatric patients with mild to moderate osteogenesis imperfecta.