Dataset Information

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.

ABSTRACT: 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?ConclusionsEfficacy 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.

SUBMITTER: Miyauchi A

PROVIDER: S-EPMC6551345 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

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.

Miyauchi Akimitsu A Dinavahi Rajani V RV Crittenden Daria B DB Yang Wenjing W Maddox Judy C JC Hamaya Etsuro E Nakamura Yoichi Y Libanati Cesar C Grauer Andreas A Shimauchi Junichiro J

Archives of osteoporosis 20190605 1

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.<h4>Purpose</h4>In the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal w ...[more]

PMID: 31168657

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Project description:Romosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off treatment or on denosumab increased or maintained BMD, respectively, and was well tolerated, providing insight into treatment sequence options. INTRODUCTION:In patients with high fracture risk, therapies that stimulate bone formation provide rapid BMD gains; currently available agents, parathyroid hormone receptor agonists, are limited to a 2-year lifetime exposure and generally used for a single treatment course. However, for long-term osteoporosis management, a second treatment course may be appropriate. Romosozumab, a therapy with the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. Here, we report efficacy and safety of a second romosozumab course. METHODS:In this phase 2, dose-finding study, postmenopausal women with low bone mass (T-score???-?2.0 and ??-?3.5) received romosozumab or placebo (month 0-24) followed by placebo or denosumab (month 24-36); participants then received a year of romosozumab (month 36-48). RESULTS:Of 167 participants who entered the month 36-48 period, 35 had been initially randomized to romosozumab 210 mg monthly. In participants who received romosozumab 210 mg monthly followed by placebo, a second romosozumab course (n?=?19) increased BMD by amounts similar to their initial treatment (month 0-12) at the lumbar spine (12.4%; 12.0%, respectively) and total hip (6.0%; 5.5%, respectively). Following denosumab, a second romosozumab course (n?=?16) increased BMD at the lumbar spine (2.3%) and maintained BMD at the total hip. Safety profiles were similar between first and second romosozumab courses. CONCLUSIONS:After 12 months off-treatment, a second romosozumab course again led to rapid and large BMD gains. Following denosumab, BMD gains with romosozumab were smaller than with initial treatment. No new safety findings were observed during the second course.

Project description:Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a T-score of > -2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline Tscore ≥ -2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH Tscore equal to -3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS Tscore equal to -3.0, the probability of achieving a T-score > -2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH T-score equal to -2.7, the probability of reaching the target Tscore with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS T-score equal to -3.0, the probability of achieving the target T-score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD T-score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline T-score falls below -2.7 (TH) and -3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project description:Romosozumab, a monoclonal anti-sclerostin antibody that has the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. In a post hoc, exploratory analysis, we evaluated the effects of romosozumab after 12 months of denosumab in postmenopausal women with low bone mass who had not received previous osteoporosis therapy. This phase 2 trial (NCT00896532) enrolled postmenopausal women with a lumbar spine, total hip, or femoral neck T-score ≤ -2.0 and ≥ -3.5. Individuals were randomized to placebo or various romosozumab dosing regimens from baseline to month 24, were re-randomized to 12 months of denosumab or placebo (months 24-36), and then all received romosozumab 210 mg monthly for 12 months (months 36-48). Results for the overall population have been previously published. Here, we present results for changes in bone mineral density (BMD) and levels of procollagen type I N-terminal propeptide (P1NP) and β-isomer of the C-terminal telopeptide of type I collagen (β-CTX) from a subset of women who were randomized to placebo for 24 months, were re-randomized to receive denosumab (n = 16) or placebo (n = 12) for 12 months, and then received romosozumab for 12 months. In women who were randomized to placebo followed by denosumab, romosozumab treatment for 12 months maintained BMD gained during denosumab treatment at the total hip (mean change from end of denosumab treatment of 0.9%) and further increased BMD gains at the lumbar spine (mean change from end of denosumab treatment of 5.3%). Upon transition to romosozumab (months 36-48), P1NP and β-CTX levels gradually returned to baseline from their reduced values during denosumab administration. Transitioning to romosozumab after 12 months of denosumab appears to improve lumbar spine BMD and maintain total hip BMD while possibly preventing the rapid increase in levels of bone turnover markers above baseline expected upon denosumab discontinuation. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project description:Background:The aim of the study was to conduct subgroup analyses of therapeutic effects of 12-month denosumab therapy on the percentage change in bone mineral density (BMD) from baseline in the lumber spine and femoral neck. Materials and methods:We prospectively evaluated the BMD of the lumbar spine and femoral neck of 100 hormone receptor-positive, clinical stage I-IIIA postoperative postmenopausal breast cancer patients, for whom treatment with aromatase inhibitors (AIs) as adjuvant endocrine therapy was scheduled. The primary endpoint was the percent change in lumbar spine BMD from baseline to 12 months. Patient subgroups were analyzed according to baseline variables that are known risk factors for bone loss, including previous AI therapy, age, time since menopause, baseline body mass index (BMI), and baseline BMD T-score. Results:At 12 months, lumbar spine BMD increased by 4.7%; the patients who were administered AI therapy prior to denosumab (n=70) demonstrated a 4.7% increase in BMD, and the patients who received denosumab at the start of AI therapy (n=30) demonstrated a 4.5% increase in BMD (p=0.8385). Additionally, 2.4% and 1.4% increases in BMD of the right and left femoral neck, respectively, were observed. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, ?65 years), time since menopause (?5, >5 years), BMI (<25, ?25 kg/m2), and T-score (?-1.0, >-1.0) of the right femoral neck were as follows: (2.2%, 2.5%, p=0.7773), (2.6%, 0.9%, p=0.1726), (2.5%, 2.3%, p=0.7594), (2.1%, 2.4%, p=0.2034), (2.1%, 2.9%, p=0.2034), and (2.3%, 2.7%, p=0.6823), respectively. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, ?65 years), time since menopause (?5, >5 years), BMI (<25, ?25 kg/m2), and T-score (?-1.0, >-1.0) of the left femoral neck were as follows: (1.0%, 1.5%, p=0.1972), (1.2%, 2.7%, p=0.2931), (1.4%, 1.3%, p=0.8817), (-0.1%, 1.6%, p=0.1766), (1.3%, 1.9%, p=0.6465), and (1.5%, 1.1%, p=0.6573), respectively. Conclusion:Twice-yearly treatment with denosumab was associated with increased BMD among Japanese women receiving adjuvant AI therapy, regardless of the baseline characteristics or skeletal site.

Project description:Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis.This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates.Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n?=?2,343 long-term; n?=?1,731 cross-over) who enrolled in the extension, missed ?1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated.For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR]?=?0.64; 95 % confidence interval (CI)?=?0.48 to 0.85, p?=?0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR?=?0.79; 95 % CI?=?0.62 to 1.00, p?=?0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD).Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Dataset Information

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.

Purpose

Methods

Results

Publications

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.

Similar Datasets

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