Effects of risedronate 5 mg/d on bone mineral density and bone turnover markers in late-postmenopausal women with osteopenia: A multinational, 24-month, randomized, double-blind, placebo-controlled, parallel-group, phase III trial

Abstract

Background: Randomized clinical trials have shown that risedronate reduces the risk for both ver- tebral and nonvertebral fractures in postmenopausal women with osteoporosis (bone mineral density [BMD] T-score, <-2.5). If left untreated, osteopenia (T-score, between -1 and -2.5) may progress to osteo- porosis. Risedronate sodium, a pyridinyl bisphospho- nate, is an antiresorptive drug approved by the US Food and Drug Administration for the prevention and treatment of osteoporosis in postmenopausal women. Although the effects of risedronate in preventing frac- tures has been established, its effects in maintaining or increasing BMD in osteopenia have not. Objective: In this clinical trial, the efficacy and tol- erability of risedronate in improving and maintaining BMD levels in late-postmenopausal women with os- teopenia were assessed. Methods: This 24-month, randomized, double- blind, placebo-controlled, parallel-group, Phase III trial was conducted at 14 study centers across Finland, The Netherlands, Norway, Spain, and Sweden. Late- postmenopausal (≥5 years from menopause) women with lumbar spine (LS) BMD T-score between -1 and -2.5 and the presence of ≥1 additional risk factor for osteo- porosis or proximal femur (Fern) BMD T-score ≤-1 were randomized to receive risedronate 5 mg (n = 114) or placebo (n = 57) PO QD for 24 months. The primary efficacy end point was the percentage change from baseline in LS BMD at study end point (24 months or last observation carried forward). Secondary efficacy end points were the percentage changes from base- line in total proximal Fern BMD and 2 bone turnover markers—urinary type I collagen cross-linked N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBAP)—at 12 months and study end point. Tolerability was assessed using reported adverse events (AEs), laboratory analysis, and physical exami- nation including vital-sign measurements. Results: A total of 171 women were included (mean [SD] age, 65.9 [6.8] years; mean [SD] LS BMD T-score,-1.82 [0.42]; risedronate group, 114 patients; placebo group, 57). At study end point, LS BMD had significantly increased from baseline in the risedronate group ( P < 0.05) but remained unchanged in the placebo group (mean [SE] %Δ, +4.49% [0.38%] and +0.05% [0.54%], respectively; P < 0.001). Between- treatment differences in mean (SE) percentage changes from baseline in LS BMD and Fem BMD were signif- icant at 12 months and study end point (LS BMD, both P < 0.001; Fem BMD, P = 0.002 and P < 0.001, respectively). At 12 months and study end point, ris- edronate use was associated with significantly reduced concentrations of uNTx and sBAP compared with placebo (both, P < 0.001). Risedronate treatment was well tolerated with regard to gastrointestinal AEs; the most frequent AEs in the risedronate group were hy- pertension (n = 13), constipation (n = 8), and hyper- cholesterolemia (n = 8). Conclusions: In these late-postmenopausal women with LS osteopenia and ≥1 additional risk factor or hip osteopenia, 24-month treatment with risedronate 5 mg/d was associated with the prevention of bone loss at the spine and hip (based on significant increases in BMD in the LS and total proximal Fem) and reduced bone resorption (based on significantly reduced concen- trations of uNTx and sBAP) and was well tolerated.