Effectiveness of romosozumab in patients with osteoporosis at high fracture risk: a Japanese real-world study.

INTRODUCTION: To describe the real-world use of romosozumab in Japan, we conducted a chart review of > 1000 Japanese patients with osteoporosis (OP) at high risk of fracture, across multiple medical institutions. MATERIALS AND METHODS: Treatment-naïve and prior OP-treatment patients who received romosozumab for 12 months followed by ≥ 6 months of sequential OP treatment were included. The primary objective described the baseline demographics and clinical characteristics; secondary objectives evaluated changes in bone mineral density (BMD) and bone turnover markers in all patients and effectiveness of romosozumab in a sub-group of treatment-naïve patients using the fracture risk assessment tool (FRAX®). RESULTS: Of the 1027 patients (92.4% female), 45.0% were treatment-naïve. The mean ± SD age of treatment-naïve versus prior OP-treatment patients was 76.8 ± 8.5 and 77.1 ± 8.5 years. The most frequent prior OP treatment was bisphosphonates (45.0%). Romosozumab treatment for 12 months increased BMD at the lumbar spine in all groups; the median percent change from baseline in lumbar spine BMD was higher in the treatment-naïve (13.4%) versus prior OP-treatment group (bisphosphonates [9.2%], teriparatide [11.3%], denosumab [DMAb, 4.5%]). DMAb, bisphosphonates, or teriparatide after romosozumab maintained the BMD gains at all skeletal sites at month 18 in treatment-naïve patients. Most treatment-naïve patients were at high risk of fracture, BMD increased consistently with romosozumab regardless of the baseline fracture risk assessed by FRAX. CONCLUSION: This large-scale, multicenter chart review provides clinically relevant insights into the profiles of patients initiating romosozumab, effectiveness of real-world romosozumab use, and sequential therapy in Japanese patients at high risk of fracture.

Efficacy and safety of romosozumab among Japanese postmenopausal women with osteoporosis and mild-to-moderate chronic kidney disease.

INTRODUCTION: This post hoc analysis of the placebo-controlled phase 3 FRAME study assessed the efficacy and safety of romosozumab in a subpopulation of Japanese postmenopausal women with osteoporosis and chronic kidney disease (CKD). MATERIALS AND METHODS: Data were analyzed by baseline estimated glomerular filtration rate (eGFR), where < 90 mL/min/1.73 m2 denoted CKD and ≥ 90 mL/min/1.73 m2 indicated normal renal function. Efficacy outcomes included percent change in lumbar spine, total hip, and femoral neck bone mineral density (BMD) at 12 months from baseline (primary) and incidence of new vertebral and non-vertebral fractures. Tolerability was also assessed. RESULTS: Of 489 Japanese patients with available eGFR data, 339 had mild-to-moderate CKD (romosozumab, n = 170; placebo, n = 169) and 150 had normal renal function (romosozumab, n = 75; placebo, n = 75). Compared with placebo, romosozumab increased lumbar spine BMD by 14.8% (95% confidence interval [CI] 13.7-15.9) and 15.2% (95% CI 13.4-16.9) in the eGFR < 90 and ≥ 90 mL/min/1.73 m2 subgroups, total hip BMD by 4.6% (95% CI 3.8-5.4) and 5.5% (95% CI 4.4-6.7), and femoral neck BMD by 4.0% (95% CI 2.9-5.2) and 5.5% (95% CI 3.8-7.1) at 12 months, respectively (all p < 0.001 vs. placebo). New vertebral fracture incidence was numerically lower with romosozumab than placebo at 12 months in both eGFR subgroups, while the incidence of adverse events was similar between subgroups. CONCLUSION: Romosozumab for 12 months is an effective and well-tolerated treatment option for Japanese patients with osteoporosis and mild-to-moderate CKD.

Romosozumab followed by denosumab in Japanese women with high fracture risk in the FRAME trial.

INTRODUCTION: This post-hoc analysis of the FRAME study investigated the long-term efficacy and safety of romosozumab followed by denosumab in postmenopausal Japanese women with osteoporosis at high fracture risk. MATERIALS AND METHODS: Data from Japanese women with a high fracture risk participating in the international, randomised, double-blind, placebo-controlled, phase 3 FRAME study were analysed. High risk of fracture was defined as ≥ 1 fragility fracture with bone mineral density (BMD) ≤ - 2.5 standard deviations [SD], > 2 prevalent vertebral fractures, prevalent semiquantitative grade 3 vertebral fracture, or lumbar spine BMD < - 3.3 SD. Endpoints included incidence of new vertebral fracture at 12, 24 and 36 months and percentage change from baseline in BMD at the lumbar spine, total hip and femoral neck. RESULTS: 187 Japanese subjects at high risk of fracture were enrolled in FRAME. Incidence of new vertebral fractures was lower with romosozumab/denosumab vs. placebo/denosumab at 12, 24 and 36 months (relative risk reduction at all timepoints: 84%; p = 0.056). BMD increases at 12, 24 and 36 months were greater in subjects receiving romosozumab/denosumab than placebo/denosumab (lumbar spine: 16.3%, 21.5% and 23.2% vs 0.4%, 8.1% and 10.4%; total hip: 4.9%, 7.9% and 8.9% vs 0.4%, 2.8% and 4.1%; femoral neck: 4.8%, 7.6% and 8.1% vs 0.3%, 3.3% and 3.7%, respectively; all p < 0.001 vs placebo/denosumab). Adverse events were generally balanced between groups. CONCLUSION: Romosozumab/denosumab in Japanese subjects at high risk of fracture resulted in significant BMD gains and numerically lower vertebral fracture rate vs. placebo/denosumab at all timepoints measured.

Correction to: Relationship between P1NP, a biochemical marker of bone turnover, and bone mineral density in patients transitioned from alendronate to romosozumab or teriparatide: a post hoc analysis of the STRUCTURE trial.

In the original publication of the article, the last row of Table 1 was published incorrectly as "Serum P1NP (µmol/L), median (IQR)b : Romosozumab, 25 (18, 34); Teriparatide, 25 (20, 33)". The correct row should be read as "Serum P1NP (µg/L), median (IQR)b : Romosozumab, 25 (18, 34); Teriparatide, 25 (20, 33)".

Relationship between P1NP, a biochemical marker of bone turnover, and bone mineral density in patients transitioned from alendronate to romosozumab or teriparatide: a post hoc analysis of the STRUCTURE trial.

INTRODUCTION: Procollagen type I N-terminal propeptide (P1NP), a bone formation marker, reportedly predicts bone mineral density (BMD) response to teriparatide treatment in treatment-naive patients with osteoporosis. Results from a randomized, phase 3, open-label, active-controlled trial- STRUCTURE-showed that in patients previously treated with bisphosphonates, romosozumab led to gains in hip BMD, which were not observed with teriparatide. This post hoc analysis investigated the comparative utility of early changes in P1NP in predicting BMD response in patients who participated in the STRUCTURE trial, which enrolled patients who switched treatment from bisphosphonates to romosozumab/teriparatide. MATERIALS AND METHODS: Postmenopausal women (aged 55-90 years) with osteoporosis who had previously taken bisphosphonates were randomized to receive open-label subcutaneous romosozumab (210 mg once monthly; n = 218) or teriparatide (20 µg once daily; n = 218) for 12 months. BMD was assessed by dual-energy X-ray absorptiometry at the proximal femur and lumbar spine (LS) at baseline and months 6 and 12. To assess the utility of P1NP, the positive predictive value of increase from baseline in P1NP of > 10 µg/L at month 1 and achievement of various thresholds of percent change from baseline in BMD at month 12 were evaluated. RESULTS: Overall, 95% (191/202) of patients in the romosozumab group and 91% (183/201) in the teriparatide group demonstrated an increase in P1NP of > 10 µg/L from baseline at month 1. Among these patients, 18% and 3% of romosozumab-treated patients versus 60% and 12% of teriparatide-treated patients showed no increase from baseline (i.e., ≤ 0%) in total hip and LS BMD, respectively, at month 12. These data indicate that in patients switching from bisphosphonates to a bone-forming therapy, increases in P1NP do not help predict the hip BMD response. Although most patients treated with either teriparatide or romosozumab showed an increase in P1NP, the majority of patients on romosozumab showed an increase in hip BMD, while more than half of the patients on teriparatide did not. Teriparatide therapy did not increase total hip BMD in the majority of patients who transitioned from bisphosphonates to teriparatide. CONCLUSIONS: Thus, increases in P1NP were not predictive of BMD response in the teriparatide group because in approximately 60% of the patients who were administered teriparatide, the hip BMD decreased independent of the change in P1NP levels.

Responsiveness of the Japanese Osteoporosis Quality of Life questionnaire in women with postmenopausal osteoporosis.

BACKGROUND: The Japanese Osteoporosis Quality of Life (JOQOL) questionnaire measures quality of life in Japanese patients with osteoporosis. However, several important aspects of the psychometric properties of individual domains, including responsiveness, have not been addressed to enable valid clinical application. This analysis examined the internal and external responsiveness of the JOQOL questionnaire. METHODS: This was a post hoc analysis of a 24-week prospective postmarketing study of raloxifene (60 mg/day) administered to postmenopausal Japanese women with osteoporosis (JapicCTI-070465). Internal responsiveness was assessed using Standardized Response Mean (SRM) statistics and changes in JOQOL domain scores. Patients were also stratified into those who did or did not achieve a minimal clinically important change (MCIC) in pain, assessed by a visual analogue scale for pain (VAS pain): comparisons were made between treated patients who achieved VAS pain reduction ≥ 20 mm versus VAS pain reduction < 20 mm. External responsiveness was assessed using Pearson's correlation coefficient (r) for changes in JOQOL domain scores with Short Form-8 Health Survey and European Quality of Life Instrument scores. RESULTS: Of 506 patients analyzed, 421 had a baseline value for VAS pain; of these, 152 patients (36.1%) had a MCIC, whereas 264 patients (62.7%) did not. The JOQOL domains pain, overall health, and falls/psychological factors had small to moderate SRM values (0.3-0.5) in all patients, but consistently showed significantly larger changes in patients whose pain score changes exceeded the MCIC. Together, these findings suggest some degree of internal responsiveness for these domains. However, activities of daily living domain had a SRM value as low as 0.2, and recreation/social activities and posture/physique domains had SRM values close to 0. Moderate correlation (defined as r ≥ 0.4 to < 0.6) was noted between the domains pain, activities of daily living, and overall health and some Short Form-8 Health Survey subscales and the European Quality of Life total score, suggesting external responsiveness of these domains. CONCLUSIONS: The inconsistent responsiveness among individual JOQOL domains in treated patients suggests the need for improving several JOQOL domains, especially the activities of daily living, recreation/social activities and posture/physique domains, before application to clinical research.

Assessing the effect of baseline status of serum bone turnover markers and vitamin D levels on efficacy of teriparatide 20 µg/day administered subcutaneously in Japanese patients with osteoporosis.

In this previously reported multicenter study, teriparatide 20 µg/day was administered to elderly Japanese subjects (93 % female; median age 70 years) with osteoporosis and at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled period, which was followed by a 12 month treatment period in which all subjects received open-label teriparatide. Subjects were randomized 2:1 to teriparatide versus placebo (teriparatide n = 137, placebo-teriparatide n = 70). This was an exploratory analysis to determine whether the baseline status of serum bone turnover markers (BTMs) and vitamin D levels affect the efficacy of teriparatide at 20 µg/day. The BTMs included were type I procollagen N-terminal pro-peptide (P1NP) and type I collagen cross-linked C-telopeptide (CTX). Changes in BMD were analyzed by subgroups: (1) tertile subgroups of BTM; (2) BTM determined by the upper limit of normal; and (3) level of vitamin D. Teriparatide increased lumbar spine BMD in all subgroups by 10 % or more through 24 months. Subgroups with higher baseline BTM levels had greater mean percent changes of lumbar spine BMD through 24 months. The baseline status of vitamin D sufficiency did not impact the mean percent change of lumbar spine BMD through 24 months. Results of this study suggest that clinically significant increases in BMD can be achieved in patients receiving teriparatide regardless of baseline BTM or vitamin D levels. Additionally, when vitamin D is coadministered, vitamin D insufficiency would not be expected to affect the overall efficacy of teriparatide.

A real-world study of treatment patterns among patients with osteoporotic fracture: analysis of a Japanese hospital database.

Health records of patients hospitalized for osteoporotic fracture were analyzed. Prior to the index hospital admission, most patients were not receiving any antiosteoporotic treatment. During the index hospitalization visit, 25.5% of patients received antiosteoporotic treatment. The most common treatment regimens were active vitamin D3, bisphosphonates, and teriparatide. PURPOSE: To examine the real-world treatment patterns and factors associated with receipt of treatment among Japanese patients with osteoporotic fracture. METHODS: We retrospectively analyzed health records of patients who were hospitalized for osteoporotic fracture between February 2016 and February 2018 in Japan. The type and duration of treatment with antiosteoporotic medications prescribed during hospital stays and after discharge were examined using descriptive statistics. Demographic and clinical factors (e.g., age, previous diagnoses, Charlson Comorbidity Index scores) associated with osteoporotic treatment were explored using multivariable logistic regression. RESULTS: A total of 112,275 patient medical records were evaluated, including 56,574 records from patients with hip fracture, 26,681 records from patients with vertebrae fracture, and 29,020 patients with non-vertebral non-hip fractures. Prior to the index hospital admission, most patients (91.7%, n = 102,919) were not receiving any antiosteoporotic treatment. For those receiving treatment, active vitamin D3 (51.1%, n = 4778) and bisphosphonates (47.5%, n = 4441) were the most common. During the index hospitalization visit, 25.5% (n = 28,678) of patients received treatment for their fracture, including active vitamin D3 (n = 17,074), bisphosphonates (n = 10,007), and teriparatide (n = 4561). Upon discharge, 41.5% (n = 46,536) of patients returned to their home and 34.3% (n = 38,542) of patients were transferred to a different hospital or medical care facility. Variables associated with receipt of treatment at follow-up included older age, previous diagnoses of osteoporosis and fracture, and higher Charlson Comorbidity Index scores. CONCLUSION: Despite osteoporotic fracture being a major health concern within older Japanese populations, treatment with antiosteoporotic medication regimens remains generally low.

Consistency of fracture risk reduction in Japanese and Caucasian osteoporosis patients treated with teriparatide: a meta-analysis.

In the global Fracture Prevention Trial, teriparatide reduced the risk of vertebral and non-vertebral fractures and significantly increased BMD. Recently, a 12-month, phase 3, randomized, multicenter, double-blind, placebo-controlled trial with BMD as a primary endpoint was conducted to assess the effects of teriparatide in Japanese subjects at high risk of fracture. Although BMD was significantly increased in the Japanese study, the study was not statistically powered to assess the anti-fracture efficacy with teriparatide treatment. A meta-analysis was carried out testing whether teriparatide had consistent anti-fracture efficacy in Japanese patients compared to that observed in the global fracture trial. Three studies in which fracture data were available from prospectively scheduled spinal radiographs were included in the analysis. A systematic review of the literature (Medline, Embase) confirmed that no studies with teriparatide had been excluded from this analysis. There was no significant heterogeneity for vertebral and non-vertebral fractures among the studies included in the meta-analysis. Odds ratio estimates (95% CI) were 0.29 (0.20, 0.43) for vertebral fracture and 0.53 (0.32, 0.86) for non-vertebral fracture. There was also a consistent effect of teriparatide to increase BMD across all studies. Furthermore, our analysis demonstrated that teriparatide-mediated increases in spine BMD accounted for 25-32% of the reduction in vertebral fracture risk in the combined population including Caucasian and Japanese patients, which was similar to that derived from Caucasian patients. These results provide evidence for the consistency of anti-fracture efficacy with teriparatide treatment in Japanese patients compared to those observed in Caucasian patients.

Safety and effectiveness profile of raloxifene in long-term, prospective, postmarketing surveillance.

This large-scale postmarketing surveillance of raloxifene (60 mg/day) was conducted to assess the safety and effectiveness of raloxifene for long-term use in postmenopausal Japanese women with osteoporosis. The baseline examination included 6,967 women (mean age, 70.4 years). Participants completed observation after 6, 12, 24, and 36 months of therapy. Adverse drug reactions (ADR) were reported in 776 participants (11.14 %), with a total of 87 serious ADR cases occurring in 76 participants (1.09 %). The most frequently reported ADRs were edema peripheral (45/6,967, 0.65 %) and venous thromboembolism (11/6,967, 0.16 %). Of the 6,967 participants, 2,784 were included in the effectiveness analysis. Lumbar spine bone mineral density (BMD) increased significantly (p < 0.001, paired t test) compared with baseline at 6, 12, 24, and 36 months (2.51 %, 2.85 %, 4.76 %, and 3.51 %, respectively). Significant decreases in serum and urinary cross-linked amino-terminal telopeptide of type I collagen (NTX) and urinary deoxypyridinoline levels from baseline were observed at 3 months, followed by a significant decrease of serum bone alkaline phosphatase at 6 months [p < 0.001 for all comparisons except serum NTX (p = 0.011), Wilcoxon signed-rank test]. Early reductions in the biochemical markers of bone turnover (BTM) observed at 3 months with raloxifene treatment correlated negatively with subsequent increases in lumbar spine BMD at 1 year (r = -0.347, p = 0.008). The incidence of any new clinical fractures within 3 years was 1.18 % (82/6,967 participants). In summary, no new signals in safety were observed in the daily use of raloxifene. Moreover, the effectiveness profile of raloxifene was confirmed in practical use by this large-scale, long-term, postmarketing surveillance.

[Evidence for osteoporosis treatment using PTH (1-34) daily subcutaneous injection].

PTH (1-34) daily subcutaneous injection is a bone anabolic agent. It has already been approved in more than 80 countries over the world (including Europe and United States) and in Japan on Jul 2010. The number of patients treated with this agent is more than 20 thousand in Japan and about one million over the world. In nonclinical studies, teriparatide was shown to have a unique bone formation-stimulating effect not seen in existing drugs. In domestic and overseas clinical studies, teriparatide was shown to have strong effects in increasing BMD, promoting remodeling of bone microstructure and suppressing the onset of fracture. Furthermore, it can increase BMD through stimulation of bone formation regardless of the nature of prior treatment or the presence/absence of responses to prior treatment. With these features, teriparatide is expected to serve as a first-line drug for management of patients with osteoporosis at high risk for fracture.

[Teriparatide: human recombinant parathyroid hormone (1-34) as a daily subcutaneous injection].

Teriparatide is a preparation of human parathyroid hormone (PTH) (1-34). It has been approved as an agent for stimulating bone formation in many foreign countries, including Europe and the United States. In Japan, it was approved in July this year. In nonclinical studies, teriparatide was shown to have a unique bone formation-stimulating effect not seen in existing drugs. In domestic and overseas clinical studies, teriparatide was shown to have strong effects in increasing BMD, promoting remodeling of bone microstructure and suppressing the onset of fracture. Furthermore, teriparatide can increase BMD through stimulation of bone formation regardless of the nature of prior treatment or the presence/absence of responses to prior treatment. With these features, teriparatide is expected to serve as a first-line drug for management of patients with osteoporosis at elevated risk for fracture.

[Pharmacological characteristics and clinical study results of romosozumab (EVENITY®; genetical recombination), a drug with novel mechanism of action to treat osteoporosis at high risk of fracture].

Romosozumab (EVENITY®) is a humanized monoclonal antibody designed to target sclerostin. Sclerostin is a glycoprotein that is secreted by osteocytes and that inhibits Wnt signaling in osteoblast lineage cells, leading to decreased bone formation by osteoblasts and increased bone resorption by osteoclasts. Romosozumab, by binding and inhibiting sclerostin, increases bone formation and decreases bone resorption. Romosozumab is known to mainly enable increase in modeling-based bone formation. In studies using ovariectomized (OVX) models of rats and cynomolgus monkeys, those administered romosozumab showed dose-dependently increased bone mass and strength. In addition, the bone-forming effect of romosozumab decreased after continued administration. In rats, romosozumab caused almost no focal osteoblast hyperplasia or benign or malignant bone tumors, presumably owing to the time-dependent decrease in the bone-forming effect. Clinical studies demonstrated inhibition of new vertebral fractures at 12 months of treatment, and increased bone mineral density at 6 months of treatment. With a dual effect on bone, increasing bone formation and decreasing bone resorption, romosozumab is expected to become a new treatment option, and was approved in January 2019 for the indication of "patients with osteoporosis at high risk for fracture".

Increased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension.

Romosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population. PURPOSE: In the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), romosozumab followed by denosumab significantly improved bone mineral density (BMD) and reduced fracture risk. This report evaluates Japanese women in FRAME. METHODS: Postmenopausal women with osteoporosis (T-score - 3.5 to - 2.5 at total hip or femoral neck) received romosozumab 210 mg or placebo subcutaneously monthly for 12 months, then each group received denosumab 60 mg subcutaneously every 6 months for 24 months. The key endpoint for Japanese women was BMD change. Other endpoints included new vertebral, clinical, and nonvertebral fracture; the subgroup analysis did not have adequate power to demonstrate statistically significant reductions. RESULTS: Of 7180 enrolled subjects, 492 (6.9%) were Japanese (247 romosozumab, 245 placebo). BMD increases from baseline were greater (P < 0.001) for romosozumab-to-denosumab than placebo-to-denosumab at the lumbar spine (36 months, 12.7%), total hip (4.2%), and femoral neck (4.1%). Fracture risk was lower through 36 months for romosozumab-to-denosumab vs placebo-to-denosumab for new vertebral (1.7% vs 4.5%; relative risk reduction (RRR) 63%, P = 0.070), clinical (3.2% vs 7.3%; RRR 53%, P = 0.072), nonvertebral (2.8% vs 6.1%; RRR 50%, P = 0.12), and all other fracture types evaluated. Rates of adverse events and positively adjudicated serious cardiovascular events were generally balanced between groups. CONCLUSIONS: Efficacy and safety for romosozumab-to-denosumab were similar between Japanese women and the overall population. The sequence of romosozumab to rebuild the skeletal foundation before transitioning to antiresorptive treatment with denosumab is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.

Treatment patterns in patients with osteoporosis at high risk of fracture in Japan: retrospective chart review.

Osteoporosis (OP) causes reduced bone strength and increases risk of fractures. Medical records from specialist clinics in Japan of postmenopausal women with OP and high risk of fracture were analysed. Majority of patients were treated for OP as recommended and were prescribed OP medications soon after high-risk OP diagnosis. PURPOSE: The incidence of osteoporosis (OP) in Japan is predicted to increase significantly in coming decades. Resultant osteoporotic fractures are a significant contributor of economic and social burden among elderly osteoporosis patients. This retrospective chart review was conducted as a response to the current evidence gap in the treatment patterns for OP patients with high risk of fracture in Japan. METHODS: This was a multi-centre retrospective chart review that analysed data extracted from the medical records of postmenopausal OP patients at high risk for fracture who received care at 11 specialist clinics and medical centers in Japan for at least 18 to 24 months. Main outcome was OP treatment patterns. RESULTS: The study included 709 eligible patients of whom 623 (87.9%) were prescribed OP medication during the study period. The most common reason for not taking OP medication was patient unwillingness to take medication. The most common OP medications prescribed initially were minodronic acid (20.1%), alendronate (19.9%), raloxifene (14.1%), weekly teriparatide acetate (12.4%) and eldecalcitol (11.4%). Majority of patients (62.1%) were still taking their initial medication at the end of the 18-24 month follow-up. CONCLUSIONS: A high percentage of patients (87.9%) in Japan received OP medications soon after their high-risk diagnosis, with bisphosphonates, selective estrogen receptor modulators and teriparatide being the predominant treatment options.

Correction to: Treatment patterns in patients with osteoporosis at high risk of fracture in Japan: retrospective chart review.

In this article it was mistakenly stated that Akimitsu Miyauchi is affiliated with both Miyauchi Medical Center, Osaka and Amgen Astellas BioPharma K.K., Tokyo. In fact he is affiliated only with Miyauchi Medical Center; he has no connection with Amgen Astellas.

Safety of 3-year raloxifene treatment in Japanese postmenopausal women aged 75 years or older with osteoporosis: a postmarketing surveillance study.

OBJECTIVE: Long-term safety of medication is a concern for older persons because they may have several comorbidities that can influence drug metabolism, efficacy, and safety. In Japan, raloxifene is an effective and well-tolerated medication for the treatment of osteoporosis in postmenopausal women, but there is little available evidence on whether raloxifene has an acceptable safety profile in older women. The objective of this post hoc analysis was to investigate the safety of raloxifene as a long-term treatment of osteoporosis in Japanese postmenopausal women aged 75 years or older. METHODS: We report a post hoc analysis of a safety dataset (6,960 participants) from a published postmarketing surveillance study (postmenopausal women treated with raloxifene 60 mg/d for ≤3 y). The safety dataset was divided into two groups: (1) women younger than 75 years at baseline (4,522 participants) and (2) women aged 75 years or older at baseline (2,438 participants). Incidence of adverse drug reactions and reactions of note in each age group were compared using Fisher's exact test. RESULTS: Approximately 10% of women in each group reported at least one adverse drug reaction. This analysis did not identify any clinically important differences in the incidence or type of adverse drug reactions reported or in reactions of note between women aged 75 years or older and younger women. CONCLUSIONS: There were no obvious additional safety concerns for women aged 75 years or older who were treated with raloxifene. The findings in this post hoc evaluation suggest no differences in adverse events in the age groups evaluated.

Quality of life in Japanese women with postmenopausal osteoporosis treated with raloxifene and vitamin D: post hoc analysis of a postmarketing study.

OBJECTIVES: To assess the effect of active vitamin D3 on quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis. RESEARCH DESIGN AND METHODS: This is a post hoc analysis of a previous prospective postmarketing observational study conducted without a comparator group. This study was conducted in 60 Japanese hospitals from September 2007 to February 2009. We compared changes from baseline in QOL and pain in patients receiving raloxifene plus active vitamin D3 with those in patients receiving raloxifene monotherapy at 8 and 24 weeks after treatment. CLINICAL TRIAL REGISTRATION: Japan Pharmaceutical Information Center (JapicCTI-070465). MAIN OUTCOME MEASURES: QOL and pain were assessed using Short Form-8 (SF-8), European Quality of Life Instrument 5 Dimensions (EQ-5D), Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), visual analogue pain scales (VAS pain), and pain frequency scores. RESULTS: A total of 506 patients were included in the post hoc analysis. Both raloxifene monotherapy (RLX, n = 354) and active vitamin D3 cotreatment (COMBI, n = 152) significantly improved QOL and reduced pain from the baseline at Week 8 and Week 24. The COMBI group had significantly greater improvements in JOQOL total score and activity of daily living (total) domain at Week 24 and last observation carried forward (LOCF) than the RLX group. The COMBI group also had significantly greater improvements in SF-8 domains of general health (at Week 8, Week 24, and LOCF), role physical (at Week 24 and LOCF), and mental health (at LOCF) than the RLX group. The COMBI group also had significantly greater reduction in VAS pain at LOCF than the RLX group (mean [SD]: RLX = -0.99 [2.72], COMBI = -1.54 [2.21], P = 0.042). CONCLUSIONS: Active vitamin D3 supplementation to raloxifene treatment for 24 weeks may have additional benefits in improving QOL and relieving pain in Japanese women with postmenopausal osteoporosis.

Systematic review of raloxifene in postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia).

PURPOSE: To systematically review the literature describing the efficacy, effectiveness, and safety of raloxifene for postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia). MATERIALS AND METHODS: Medline via PubMed and Embase was systematically searched using prespecified terms. Retrieved publications were screened and included if they described randomized controlled trials or observational studies of postmenopausal Japanese women with osteoporosis or osteopenia treated with raloxifene and reported one or more outcome measures (change in bone mineral density [BMD]; fracture incidence; change in bone-turnover markers, hip structural geometry, or blood-lipid profile; occurrence of adverse events; and change in quality of life or pain). Excluded publications were case studies, editorials, letters to the editor, narrative reviews, or publications from non-peer-reviewed journals; multidrug, multicountry, or multidisease studies with no drug-, country-, or disease-level analysis; or studies of participants on dialysis. RESULTS: Of the 292 publications retrieved, 15 publications (seven randomized controlled trials, eight observational studies) were included for review. Overall findings were statistically significant increases in BMD of the lumbar spine (nine publications), but not the hip region (eight publications), a low incidence of vertebral fracture (three publications), decreases in markers of bone turnover (eleven publications), improved hip structural geometry (two publications), improved blood-lipid profiles (five publications), a low incidence of hot flushes, leg cramps, venous thromboembolism, and stroke (12 publications), and improved quality of life and pain relief (one publication). CONCLUSION: Findings support raloxifene for reducing vertebral fracture risk by improving BMD and reducing bone turnover in postmenopausal Japanese women with osteoporosis or osteopenia. Careful consideration of fracture risk and the risk-benefit profile of antiosteoporosis medications is required when managing patients with osteoporosis.

Quality of life in raloxifene-treated Japanese women with postmenopausal osteoporosis: a prospective, postmarketing observational study.

OBJECTIVE: To assess changes in quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis. RESEARCH DESIGN AND METHODS: This prospective, postmarketing observational study was conducted at 60 Japanese hospitals from September 2007 to February 2009 and included Japanese women with postmenopausal osteoporosis who were new to standard treatment with raloxifene (60 mg/day). Primary outcome measures (QOL and pain) were assessed using the Short Form-8 (SF-8), European Quality of Life Instrument (EQ-5D), osteoporosis-specific Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), a visual analogue scale (VAS-pain), and a pain frequency survey. Assessments were performed at baseline and 8 (except JOQOL) and 24 weeks after first administration of raloxifene. Adverse drug reactions were recorded. Japan Pharmaceutical Information Center registration number: JapicCTI-070465. RESULTS: A total of 506 participants, mean (±standard deviation [SD]) age = 70.7 ± 8.7 years, completed ≥1 follow-up assessment and were included in the analyses. All QOL scores increased from baseline during follow-up. All SF-8 domain scores increased significantly from baseline after 8 and 24 weeks (P < 0.001). Mean (±SD) EQ-5D scores increased significantly from baseline (0.70 ± 0.17) by 0.05 ± 0.15 after 8 weeks and 0.07 ± 0.17 after 24 weeks (P < 0.001). The mean (±SD) total JOQOL score increased significantly from baseline (66.8 ± 16.5) by 3.8 ± 11.3 after 24 weeks (P < 0.001). The percentage of participants with a ≥20 mm reduction in VAS-pain was 32.6% (120/368) and 39.5% (115/291) after 8 and 24 weeks, respectively. The frequency of pain reported by participants decreased after 8 and 24 weeks. Forty adverse drug reactions were reported by 34 participants. LIMITATIONS: Limitations include the lack of a control group, the possibility of the changes being due to the natural disease course, and potential selection bias. CONCLUSIONS: Our findings suggest that standard treatment with raloxifene improves QOL and relieves pain in Japanese women with postmenopausal osteoporosis in a real-world clinical setting.