Factors associated with inadequate responses to risedronate in Japanese patients with osteoporosis.

Factors associated with an inadequate response (IR) to bisphosphonates have been reported in many countries, but not in Japan, where the approved dose is half the global dose. We analyzed factors associated with IR to risedronate in Japanese patients with osteoporosis. This was a post hoc analysis of 1261 Japanese osteoporosis patients who received risedronate for 1 year in phase III trials. IR was defined as more than one new vertebral fracture (VF) and/or negative change in lumbar spine bone mineral density (BMD) at 1 year. Various baseline and follow-up variables were examined for potential contribution to IR. Of the 1261 subjects, 118 exhibited an IR. At baseline, IR was associated with a higher BMD, lower levels of bone turnover markers (BTM) (serum bone-specific alkaline phosphatase, urinary N-terminal telopeptide of type 1 collagen and C-terminal telopeptide of type 1 collagen), and serum 25-hydroxyvitamin D [25(OH)D] below 16 ng/mL. BTM changes were blunted at 6 months in subjects with IR. On simple regression analysis, all the above variables and poor drug adherence were associated with an IR. On multivariate regression analysis, factors associated with IR were high BMD, vitamin D deficiency at baseline and low BTM at baseline, or a decreased BTM response at 6 months. Low serum 25(OH)D and BTM as well as high BMD at baseline were independent predictors of an IR to risedronate in Japan. These results emphasize the importance of the assessment of serum 25(OH)D and BTM in the management of osteoporosis with bisphosphonates.

Efficacy on the risk of vertebral fracture with administration of once-weekly 17.5 mg risedronate in Japanese patients of established osteoporosis with prevalent vertebral fractures: a 156-week longitudinal observational study in daily practice.

Currently, the only available evidence for the efficacy of once-weekly 17.5 mg risedronate in preventing vertebral fractures was obtained in a 48-week study in Japan. We performed a 156-week prospective, longitudinal, observational study to determine the efficacy of the 17.5 mg risedronate in preventing vertebral fractures. We included Japanese patients with established osteoporosis who were older than 50 years and had radiographically confirmed vertebral fractures. The primary endpoint was the incidence of vertebral fractures every 24 weeks, with the final interval spanning 36 weeks. We also calculated the change in bone mineral density of the lumbar spine (L2-4 BMD) and urinary N-telopeptide of type I collagen (u-NTX), and assessed the incidence of adverse drug reactions and the drug adherence rate. Data from 241 patients were available for analysis of vertebral fracture prevention. The incidence rate of vertebral fractures decreased in a time-dependent manner (P = 0.0006; Poisson regression analysis). The risk ratio (fracture incidence per 100 person-years in the final 36 weeks versus that in the first 24 weeks) was 0.21 (95 % confidence interval 0.08-0.55). Compared to baseline values, L2-4 BMD increased by 6.41 % at 156 weeks, while u-NTX decreased by 36 % at 24 weeks and was maintained thereafter (P < 0.0001). The incidence rate of adverse drug reactions was 9.18 %. Drug adherence rates assessed every 4 weeks were over 90 %. Our results indicate that 156 weeks of treatment with once-weekly 17.5 mg risedronate effectively reduced the risk of vertebral fracture in Japanese patients with established osteoporosis older than 50 years.

Risedronate therapy in patients with mild-to-moderate chronic kidney disease with osteoporosis: post-hoc analysis of data from the risedronate phase III clinical trials.

BACKGROUND: The clinical effect of bisphosphonate treatment has not been clearly evaluated by kidney function in Japanese Chronic Kidney Disease (CKD) patients with osteoporosis. This study analyzed the data from three risedronate Japanese phase III trials. The clinical effect of risedronate therapy was evaluated in CKD patients with osteoporosis. METHODS: The Japanese clinical trials involved 852 subjects who received risedronate (2.5 mg once daily or 17.5 mg once weekly) and whose estimated glomerular filtration rate (eGFR) were calculable and at ≥ 30 mL/min. The subjects were divided into subgroups according to the eGFR level: ≥ 90 mL/min/1.73 m2, ≥ 60 to < 90 mL/min/1.73 m2, ≥ 30 to < 60 mL/min/1.73 m2. Lumbar spine bone mineral density (BMD), bone turnover markers (BTMs) and adverse events were evaluated at 48 weeks. RESULTS: Adverse event incidence was similar among three subgroups. There was also no exacerbation of impaired kidney function associated with risedronate administration in the subjects with eGFR above 30 mL/min/1.73 m2. Risedronate administration induced a significant increase in lumbar spine BMD and significant inhibition of BTMs in three subgroups. CONCLUSIONS: The risedronate therapy showed similar clinical effects in CKD patients with osteoporosis compared to those without CKD.

Efficacy and Safety of Risedronate in Osteoporosis Subjects with Comorbid Diabetes, Hypertension, and/or Dyslipidemia: A Post Hoc Analysis of Phase III Trials Conducted in Japan.

Many osteoporotics have comorbid diabetes mellitus (DM), hypertension (HT), and dyslipidemia (DL). However, whether such comorbidities alter response to anti-osteoporotic treatment is unknown. We did post hoc analyses of combined data from three risedronate Japanese phase III trials to determine whether the presence of DM, HT, or DL affects its efficacy and safety. Data from 885 subjects who received 48-week treatment with risedronate were collected and combined from the three phase III trials. They were divided into two groups by the presence or absence of comorbidities: DM (n = 53) versus non-DM (n = 832); HT (n = 278) versus non-HT (n = 607); and DL (n = 292) versus non-DL (n = 593). Bone mineral density (BMD), urinary type 1 collagen N-telopeptide (uNTX), and serum bone-specific alkaline phosphatase (BAP) were measured at baseline and sequentially until 48 weeks. BMD or bone markers were not different between any of the two groups. Overall, BMD was increased by 5.52%, and uNTX and BAP were decreased by 35.4 and 33.8%, respectively. Some bone markers were slightly lower in DM and DL subjects, but the responses to risedronate were not significantly different. Statin users had lower uNTX and BAP, but showed no difference in the treatment response. All the other medications had no apparent effect. Adverse event incidence was marginally higher in DL compared with non-DL (Relative risk 1.06; 95% confidence interval 1.01-1.11), but was not related to increase in any specific events. Risedronate shows consistent safety and efficacy in suppressing bone turnover and increasing BMD in osteoporosis patients with comorbid DM, HT, and/or DL.

Assessment of baseline bone turnover marker levels and response to risedronate treatment: Data from a Japanese phase III trial.

BACKGROUND: Risedronate increases bone mineral density (BMD) and reduces fracture risk, but treatment response may depend on the baseline state of bone turnover. Data regarding the selection of therapeutic drugs or the prediction of therapeutic effects with baseline levels of bone turnover markers (BTMs) as a reference are insufficient. We hypothesized that when the baseline levels of BTMs are higher, baseline BMD might be lower, changes in BMD at 12 months after risedronate treatment might be higher, and the reduction of fracture incidence might be greater. This study aimed to analyze the data of a phase III clinical trial of risedronate from Japan to investigate the relationships between baseline BTM levels and (1) baseline BMD, (2) changes in BMD at 12 months after the start of treatment, and (3) the incidence of new vertebral fractures. METHODS: This post-hoc analysis included 788 postmenopausal women with osteoporosis whose baseline BTM levels as well as baseline and endpoint BMDs were measured. Relationships between baseline BTM levels and BMD at baseline and 12 months after risedronate treatment and new vertebral fractures were examined. One-way analysis of variance, two-tailed Student's t-test, and Fisher's exact test were used to analyze the data. RESULTS: Baseline BMD showed a significant upward trend when baseline BTM levels were lower in the analysis by tertiles. New vertebral fractures tended to occur in patients with prevalent vertebral fractures, but the relationship between new fractures and BTM levels was not statistically significant. Regardless of BTM types, BMD percentage increments (%) and increments (g/cm2) with the 12-month treatment were high when pretreatment BTM levels were high (P < 0.0001), and a >5.0% increase in BMD was observed even if baseline BTM levels were within the normal range. A new vertebral fracture occurred in only six patients (0.77%), and there was not enough statistical power to clarify the relationship between baseline BTM levels and fracture risk reduction. CONCLUSIONS: When pretreatment BTM levels increased, baseline BMD tended to be lower and the increase in BMD with 12-month risedronate treatment was higher. However, BMD could still be increased even if the baseline BTM levels are within the normal range. Combined with available evidence, baseline BTMs may not have an important role in deciding the optimal therapy. To elucidate the relationship between baseline BTM levels and long-term fracture risk, it will be necessary to conduct more large-scale studies with a longer follow-up period in severe osteoporotic patients with a high fracture risk. MINI ABSTRACT: We evaluated the significance of baseline bone turnover markers in the response to risedronate treatment. The increase in the bone mineral density (BMD) with the 12-month treatment may be higher when the state of bone turnover at baseline is higher, and BMD could still be increased even if the baseline bone turnover is within the normal range.