Romosozumab

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  • a single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of Romosozumab
    Osteoporosis International, 2020
    Co-Authors: Michael R Mcclung, Judy Maddox, Paul D. Meisner, Jacques P Brown, Bente L Langdahl, M. A. Bolognese, J.-y. Reginster, M. Rojeski, Andreas Grauer
    Abstract:

    This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following Romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with Romosozumab treatment and was well tolerated. INTRODUCTION Follow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of Romosozumab therapy. We evaluated the use of zoledronate following Romosozumab treatment. METHODS This phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various Romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label Romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and β-CTX) and safety were evaluated for 24 months, up to month 72. RESULTS A total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and β-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and β-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed. CONCLUSION A zoledronate follow-on regimen can maintain robust BMD gains achieved with Romosozumab treatment.

  • 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
    Journal of Bone and Mineral Metabolism, 2020
    Co-Authors: Junichi Takada, Cassandra E. Milmont, Akimitsu Miyauchi, Rajani V Dinavahi, C Libanati, Etsuro Hamaya, Yoichi Nakamura, Toshiyasu Hirama, Andreas Grauer
    Abstract:

    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. 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. 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. 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.

  • 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.
    Journal of bone and mineral metabolism, 2020
    Co-Authors: Junichi Takada, Cassandra E. Milmont, Cesar Libanati, Akimitsu Miyauchi, Etsuro Hamaya, Yoichi Nakamura, Rajani Dinavahi, Toshiyasu Hirama, Andreas Grauer
    Abstract:

    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)".

  • bone mineral density gains with a second 12 month course of Romosozumab therapy following placebo or denosumab
    Osteoporosis International, 2019
    Co-Authors: David L Kendler, Judy Maddox, Henry G Bone, F Massari, Evelien Gielen, Santiago Palacios, Rajani V Dinavahi, C Libanati, Andreas Grauer
    Abstract:

    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. 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. 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). 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. 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.

  • The Effect of 1 Year of Romosozumab on the Incidence of Clinical Vertebral Fractures in Postmenopausal Women With Osteoporosis: Results From the FRAME Study.
    JBMR plus, 2019
    Co-Authors: Piet Geusens, Cassandra E. Milmont, Akimitsu Miyauchi, Andreas Grauer, Jonathan D. Adachi, Mary Oates, Peter R Ebeling, Carlos Augusto Perez Nino, Marise Lazaretti-castro, Cesar Libanati
    Abstract:

    : Radiographic vertebral fractures (VFxs) are the most common fractures in osteoporosis and are associated with increased morbidity, mortality, and costs. A subset of VFxs manifest clinically, usually with a sudden onset of severe back pain. Romosozumab is a monoclonal antibody that binds and inhibits sclerostin, increasing bone formation and decreasing bone resorption, leading to rapid and large increases in bone density and strength and reduction in fracture risk. The FRAME (Fracture Study in Postmenopausal Women with Osteoporosis) study of postmenopausal women with osteoporosis demonstrated a significant reduction in new VFxs with Romosozumab versus placebo. Here, we report the effect of Romosozumab versus placebo on clinical VFx incidence over 12 months in women reporting back pain suggestive of VFxs. FRAME enrolled 7180 postmenopausal women with osteoporosis, mean age 70.9 years (hip T-score -2.5 to -3.5). In the first year of the study, women received monthly Romosozumab 210 mg (n = 3589) or placebo (n = 3591). At regular monthly visits, women reporting back pain suggestive of a clinical VFx had a confirmatory spine X-ray. Clinical VFx risk in the Romosozumab group versus the placebo group was calculated by Cox-proportional hazards model. Of 119 women in FRAME with back pain suggestive of a clinical VFx over 12 months, 20 were confirmed to have experienced a new/worsening VFx. Three women receiving Romosozumab had a clinical VFx (

C Libanati - One of the best experts on this subject based on the ideXlab platform.

  • t score as an indicator of fracture risk during treatment with Romosozumab or alendronate in the arch trial
    Journal of Bone and Mineral Research, 2020
    Co-Authors: Felicia Cosman, Daria B. Crittenden, Wenjing Yang, Toshio Matsumoto, Peter R Ebeling, Michael E Lewiecki, Eric Hesse, Nicola Napoli, Maria Rojeski, C Libanati
    Abstract:

    : In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of Romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (Romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with Romosozumab versus 2.9% (T-score change 0.15) with alendronate (p -2.5 increased from 34% at baseline to 55% after 1 year of Romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving Romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of Romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

  • 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
    Journal of Bone and Mineral Metabolism, 2020
    Co-Authors: Junichi Takada, Cassandra E. Milmont, Akimitsu Miyauchi, Rajani V Dinavahi, C Libanati, Etsuro Hamaya, Yoichi Nakamura, Toshiyasu Hirama, Andreas Grauer
    Abstract:

    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. 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. 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. 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.

  • bone mineral density gains with a second 12 month course of Romosozumab therapy following placebo or denosumab
    Osteoporosis International, 2019
    Co-Authors: David L Kendler, Judy Maddox, Henry G Bone, F Massari, Evelien Gielen, Santiago Palacios, Rajani V Dinavahi, C Libanati, Andreas Grauer
    Abstract:

    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. 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. 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). 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. 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.

  • the effect of 1 year of Romosozumab on the incidence of clinical vertebral fractures in postmenopausal women with osteoporosis results from the frame study
    JBMR plus, 2019
    Co-Authors: Piet Geusens, Cassandra E. Milmont, Akimitsu Miyauchi, Andreas Grauer, Jonathan D. Adachi, Mary Oates, Marise Lazaretticastro, Peter R Ebeling, Carlos Augusto Perez Nino, C Libanati
    Abstract:

    : Radiographic vertebral fractures (VFxs) are the most common fractures in osteoporosis and are associated with increased morbidity, mortality, and costs. A subset of VFxs manifest clinically, usually with a sudden onset of severe back pain. Romosozumab is a monoclonal antibody that binds and inhibits sclerostin, increasing bone formation and decreasing bone resorption, leading to rapid and large increases in bone density and strength and reduction in fracture risk. The FRAME (Fracture Study in Postmenopausal Women with Osteoporosis) study of postmenopausal women with osteoporosis demonstrated a significant reduction in new VFxs with Romosozumab versus placebo. Here, we report the effect of Romosozumab versus placebo on clinical VFx incidence over 12 months in women reporting back pain suggestive of VFxs. FRAME enrolled 7180 postmenopausal women with osteoporosis, mean age 70.9 years (hip T-score -2.5 to -3.5). In the first year of the study, women received monthly Romosozumab 210 mg (n = 3589) or placebo (n = 3591). At regular monthly visits, women reporting back pain suggestive of a clinical VFx had a confirmatory spine X-ray. Clinical VFx risk in the Romosozumab group versus the placebo group was calculated by Cox-proportional hazards model. Of 119 women in FRAME with back pain suggestive of a clinical VFx over 12 months, 20 were confirmed to have experienced a new/worsening VFx. Three women receiving Romosozumab had a clinical VFx (<0.1% of 3589 women) versus 17 (0.5% of 3591 women) receiving placebo resulting in a reduction in clinical VFx risk of 83% in the Romosozumab group versus placebo through 12 months (HR 0.17; 95% CI, 0.05 to 0.58; p = 0.001). In the three Romosozumab-treated women, clinical VFxs occurred within the first 2 months of the study with no further clinical VFxs throughout the year. Romosozumab treatment for 12 months was associated with rapid and large reductions in clinical VFx risk versus placebo. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

  • bone forming and antiresorptive effects of Romosozumab in postmenopausal women with osteoporosis bone histomorphometry and microcomputed tomography analysis after 2 and 12 months of treatment
    Journal of Bone and Mineral Research, 2019
    Co-Authors: P Chavassieux, C Libanati, J. P. Brown, Roland Chapurlat, Nathalie Porteromuzy, Jeanpaul Roux, Pedro Garcia, Rogely W Boyce, Andrea Wang, Andreas Grauer
    Abstract:

    Sclerostin, a protein produced by osteocytes, inhibits bone formation. Administration of sclerostin antibody results in increased bone formation in multiple animal models. Romosozumab, a humanized sclerostin antibody, has a dual effect on bone, transiently increasing serum biochemical markers of bone formation and decreasing serum markers of bone resorption, leading to increased BMD and reduction in fracture risk in humans. We aimed to evaluate the effects of Romosozumab on bone tissue. In a subset of 107 postmenopausal women with osteoporosis in the multicenter, international, randomized, double‐blind, placebo‐controlled Fracture Study in Postmenopausal Women with Osteoporosis (FRAME), transiliac bone biopsies were performed either after 2 (n = 34) or 12 (n = 73) months of treatment with 210 mg once monthly of Romosozumab or placebo to evaluate histomorphometry and microcomputed tomography‐based microarchitectural endpoints. After 2 months, compared with either baseline values assessed after a quadruple fluorochrome labeling or placebo, significant increases (P < 0.05 to P < 0.001) in dynamic parameters of formation (median MS/BS: Romosozumab 1.51% and 5.64%; placebo 1.60% and 2.31% at baseline and month 2, respectively) were associated with a significant decrease compared with placebo in parameters of resorption in cancellous (median ES/BS: placebo 3.4%, Romosozumab 1.8%; P = 0.022) and endocortical (median ES/BS: placebo 6.3%, Romosozumab 1.6%; P = 0.003) bone. At 12 months, cancellous bone formation was significantly lower (P < 0.05 to P < 0.001) in Romosozumab versus placebo and the lower values for resorption endpoints seen at month 2 persisted (P < 0.001), signaling a decrease in bone turnover (P = 0.006). No significant change was observed in periosteal and endocortical bone. This resulted in an increase in bone mass and trabecular thickness with improved trabecular connectivity, without significant modification of cortical porosity at month 12. In conclusion, Romosozumab produced an early and transient increase in bone formation, but a persistent decrease in bone resorption. Antiresorptive action eventually resulted in decreased bone turnover. This effect resulted in significant increases in bone mass and improved microarchitecture.© 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Jacques P Brown - One of the best experts on this subject based on the ideXlab platform.

  • a single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of Romosozumab
    Osteoporosis International, 2020
    Co-Authors: Michael R Mcclung, Judy Maddox, Paul D. Meisner, Jacques P Brown, Bente L Langdahl, M. A. Bolognese, J.-y. Reginster, M. Rojeski, Andreas Grauer
    Abstract:

    This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following Romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with Romosozumab treatment and was well tolerated. INTRODUCTION Follow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of Romosozumab therapy. We evaluated the use of zoledronate following Romosozumab treatment. METHODS This phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various Romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label Romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and β-CTX) and safety were evaluated for 24 months, up to month 72. RESULTS A total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and β-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and β-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed. CONCLUSION A zoledronate follow-on regimen can maintain robust BMD gains achieved with Romosozumab treatment.

  • effects of 24 months of treatment with Romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density a randomized double blind phase 2 parallel group study
    Journal of Bone and Mineral Research, 2018
    Co-Authors: Michael R Mcclung, Paul D. Meisner, Henry G Bone, Jacques P Brown, Adolfo Diezperez, H Resch, John Caminis, Michael A Bolognese, Stefan Goemaere, J R Zanchetta
    Abstract:

    : Over 12 months, Romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with Romosozumab, discontinuation of Romosozumab, alendronate followed by Romosozumab, and Romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤-2.0 and ≥-3.5 were enrolled and randomly assigned to placebo, one of five Romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by Romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to Romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with Romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving Romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With Romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker β-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and β-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of Romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

  • Romosozumab sclerostin monoclonal antibody versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy a randomised open label phase 3 trial
    The Lancet, 2017
    Co-Authors: Bente L Langdahl, Daria B. Crittenden, C Libanati, Jacques P Brown, Michael A Bolognese, Klaus Engelke, N Daizadeh, Eva Dokoupilova, Joel S Finkelstein
    Abstract:

    Summary Background Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of Romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. Methods This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of −2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous Romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 μg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. Findings Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to Romosozumab (n=218) or teriparatide (n=218). 206 patients in the Romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the Romosozumab group and −0·6% (−1·0 to −0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [ vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on Romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the Romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. Interpretation Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, Romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. Funding Amgen, Astellas, and UCB Pharma.

  • greater gains in spine and hip strength for Romosozumab compared with teriparatide in postmenopausal women with low bone mass
    Journal of Bone and Mineral Research, 2017
    Co-Authors: Tony M Keaveny, Daria B. Crittenden, Andreas Grauer, Jacques P Brown, Michael A Bolognese, Harry K Genant, Klaus Engelke, Beatriz Oliveri, Bente L Langdahl, Cesar Libanati
    Abstract:

    : Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naive postmenopausal women with low bone mass, Romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded Romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L1 vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for Romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p < 0.0001); changes in femoral strength for Romosozumab showed similar but smaller changes, increasing more with Romosozumab versus teriparatide (3.6% versus -0.7%; p = 0.027), and trending higher versus placebo (3.6% versus -0.1%; p = 0.059). Compartmental analysis revealed that the bone-strengthening effects for Romosozumab were associated with positive contributions from both the cortical and trabecular bone compartments at both the lumbar spine and hip. Taken together, these findings suggest that Romosozumab may offer patients with osteoporosis a new bone-forming therapeutic option that increases both vertebral and femoral strength within 12 months. © 2017 American Society for Bone and Mineral Research.

  • Greater Gains in Spine and Hip Strength for Romosozumab Compared With Teriparatide in Postmenopausal Women With Low Bone Mass
    Journal of Bone and Mineral Research, 2017
    Co-Authors: Tony M Keaveny, Daria B. Crittenden, Jacques P Brown, Michael A Bolognese, Harry K Genant, Klaus Engelke, Beatriz Oliveri, Bente L Langdahl, Andreas Grauer
    Abstract:

    : Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naive postmenopausal women with low bone mass, Romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded Romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L1 vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for Romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p 

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  • t score as an indicator of fracture risk during treatment with Romosozumab or alendronate in the arch trial
    Journal of Bone and Mineral Research, 2020
    Co-Authors: Felicia Cosman, Daria B. Crittenden, Wenjing Yang, Toshio Matsumoto, Peter R Ebeling, Michael E Lewiecki, Eric Hesse, Nicola Napoli, Maria Rojeski, C Libanati
    Abstract:

    : In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of Romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (Romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with Romosozumab versus 2.9% (T-score change 0.15) with alendronate (p -2.5 increased from 34% at baseline to 55% after 1 year of Romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving Romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of Romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

  • T-Score as an Indicator of Fracture Risk During Treatment With Romosozumab or Alendronate in the ARCH Trial.
    Journal of Bone and Mineral Research, 2020
    Co-Authors: Felicia Cosman, Daria B. Crittenden, E M Lewiecki, Wenjing Yang, Toshio Matsumoto, Peter R Ebeling, Eric Hesse, Nicola Napoli, Maria Rojeski, Cesar Libanati
    Abstract:

    : In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of Romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (Romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with Romosozumab versus 2.9% (T-score change 0.15) with alendronate (p -2.5 increased from 34% at baseline to 55% after 1 year of Romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving Romosozumab had a 75% reduction in new or worsening vertebral fracture (p

  • 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
    Archives of Osteoporosis, 2019
    Co-Authors: Akimitsu Miyauchi, Daria B. Crittenden, Judy Maddox, Andreas Grauer, Rajani V Dinavahi, C Libanati, Wenjing Yang, Etsuro Hamaya, Yoichi Nakamura, Junichiro Shimauchi
    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. 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. 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. 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. 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.

  • 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
    Archives of Osteoporosis, 2019
    Co-Authors: Akimitsu Miyauchi, Daria B. Crittenden, Judy Maddox, Cesar Libanati, Andreas Grauer, Rajani V Dinavahi, Wenjing Yang, Etsuro Hamaya, Yoichi Nakamura, Junichiro Shimauchi
    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. 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. 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. Of 7180 enrolled subjects, 492 (6.9%) were Japanese (247 Romosozumab, 245 placebo). BMD increases from baseline were greater (P 

  • Romosozumab frame study a post hoc analysis of the role of regional background fracture risk on nonvertebral fracture outcome
    Journal of Bone and Mineral Research, 2018
    Co-Authors: Felicia Cosman, Daria B. Crittenden, Cassandra E. Milmont, Paul D. Meisner, Serge Ferrari, Cristiano A F Zerbini, C Libanati, Michael E Lewiecki, Juan Jallerraad, Andreas Grauer
    Abstract:

    : In the pivotal Fracture Study in Postmenopausal Women with Osteoporosis (FRAME; NCT01575834), 1 year of the bone-forming agent Romosozumab significantly reduced new vertebral and clinical fracture risk versus placebo. Nonvertebral fracture risk was not significantly reduced in the overall population, influenced by a low placebo-group fracture rate, observed particularly in the highest-enrolling region of Latin America. In year 1 of FRAME, postmenopausal women with a T-score of -2.5 to -3.5 at the total hip or femoral neck were randomized to subcutaneous Romosozumab 210 mg or placebo once monthly for 12 months. Of 7180 randomized women, 43% were from Latin America, largely Colombia and Brazil. Prespecified analyses assessed fracture risk reductions by geographic regions. A significant treatment-by-geographic region interaction for the clinical (p = 0.029) and nonvertebral fracture (p = 0.042) endpoints led to further characterization of the Latin American population and comparison with the remaining study population, grouped post hoc as rest-of-world. Nonvertebral fracture efficacy in the overall population was also assessed by baseline fracture risk using the Fracture Risk Assessment Tool (FRAX). Romosozumab significantly and consistently reduced new vertebral fracture risk in Latin America (70% reduction; p = 0.014) and rest-of-world (74% reduction; p < 0.001). For nonvertebral fracture, risk reductions were observed in rest-of-world (42% reduction; p = 0.012), with no treatment effect observed in Latin America, where background nonvertebral fracture risk was low (1.2% in the placebo group). Consistent with this finding, in the overall population, greater reductions in nonvertebral fracture risk were observed among women with higher FRAX scores. These findings suggest that fracture risk assessment should consider regional factors in addition to classical risk factors, such as bone mineral density. In women at high risk for fracture, Romosozumab reduced nonvertebral fracture risk within 1 year. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

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  • a single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of Romosozumab
    Osteoporosis International, 2020
    Co-Authors: Michael R Mcclung, Judy Maddox, Paul D. Meisner, Jacques P Brown, Bente L Langdahl, M. A. Bolognese, J.-y. Reginster, M. Rojeski, Andreas Grauer
    Abstract:

    This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following Romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with Romosozumab treatment and was well tolerated. INTRODUCTION Follow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of Romosozumab therapy. We evaluated the use of zoledronate following Romosozumab treatment. METHODS This phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various Romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label Romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and β-CTX) and safety were evaluated for 24 months, up to month 72. RESULTS A total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and β-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and β-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed. CONCLUSION A zoledronate follow-on regimen can maintain robust BMD gains achieved with Romosozumab treatment.

  • op0297 efficacy and safety of Romosozumab among postmenopausal women with osteoporosis and mild to moderate chronic kidney disease
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Paul D Miller, Akimitsu Miyauchi, Jonathan D. Adachi, Evelien Gielen, Arkadi A Chines, Bente L Langdahl, Angela M. Cheung, B H Albergaria, Mary Oates
    Abstract:

    Background: Osteoporosis and renal insufficiency are coexisting disease states in a substantial proportion of postmenopausal women. Since bisphosphonates are generally contraindicated in patients with estimated glomerular filtration rate (eGFR) Objectives: To determine if baseline renal function affects the efficacy and safety of Romosozumab. Methods: We performed post hoc analyses of two clinical trials of Romosozumab in postmenopausal women with osteoporosis. In ARCH (NCT01631214), 4,093 patients were randomised 1:1 to Romosozumab 210 mg monthly or alendronate 70 mg weekly for 12 months (mean age: 74.3 years; 96.1% with prevalent vertebral fractures [VFx]). In FRAME (NCT01575834), 7,180 patients were randomised 1:1 to Romosozumab 210 mg or placebo monthly for 12 months (mean age: 70.9 years; 18.3% with prevalent VFx). For these analyses, patients were categorised by baseline eGFR (mL/min/1.73m2): normal renal function (eGFR ≥90), mild renal insufficiency (eGFR 60–89), or moderate renal insufficiency (eGFR 30–59). Least squares mean (LSM) percent change from baseline in bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck; incidence of new VFx and adverse events (AEs); and changes in renal function were assessed for each eGFR category at Month 12 of the double-blind treatment period. Results: At baseline, most patients had mild/moderate renal insufficiency: 84% in ARCH, 88% in FRAME. In both studies, change from baseline in BMD was significantly higher in the Romosozumab group across baseline eGFR categories (Figure). There was an interaction between BMD increase and renal function, and although BMD increase was not as large in women with impaired renal function, differences between Romosozumab and control groups remained significant (Figure). In ARCH, among patients with eGFR ≥90, 60–89, and 30–59, the incidence of new VFx (Romosozumab vs alendronate) at Month 12 was 3.3% vs 7.3%, 3.2% vs 3.9%, and 3.4% vs 6.2% in ARCH. In FRAME, the incidence of new VFx (Romosozumab vs placebo) at Month 12 was 0.5% vs 3.0%, 0.4% vs 1.5%, and 0.6% vs 2.1%. In both studies, the incidences of AEs and serious AEs were similar in both treatment groups within and across eGFR categories. AEs of mild-to-moderate hypocalcaemia (investigator reported) occurred in two patients in ARCH (one Romosozumab [eGFR 60–89] and one alendronate [eGFR ≥90]), and one patient in FRAME (Romosozumab [eGFR 60–89]). Five patients in ARCH (all in the alendronate group) and 19 patients in FRAME (14 Romosozumab, 5 placebo) had decreases in serum Ca levels (albumin adjusted); in the Romosozumab group all were mild ( Conclusion: The efficacy and safety of Romosozumab vs alendronate or placebo was similar among postmenopausal women with osteoporosis and different levels of renal function. Acknowledgments: This study was funded by Amgen, Astellas and UCB Pharma. Editorial services were provided by Costello Medical. Disclosure of Interests: Paul Miller Grant/research support from: Amgen, Radius Health, Ultragenyx, Consultant of: Amgen, Radius Health, Jonathan Adachi Consultant of: Amgen, Speakers bureau: Amgen, Ben-Hur Albergaria Consultant of: Amgen Inc., Eli Lilly, Speakers bureau: Amgen Inc., Eli Lilly, Angela M Cheung Consultant of: Amgen, Eli Lilly, Arkadi Chines Shareholder of: Amgen Inc., Employee of: Amgen Inc., Evelien Gielen Consultant of: Amgen Inc., Takeda, Sandoz and UCB Pharma, Speakers bureau: Amgen Inc., Takeda, Sandoz and UCB Pharma, Bente Langdahl Grant/research support from: Amgen, NovoNordisk, Consultant of: Amgen Inc., Eli Lilly, UCB Pharma, Akimitsu Miyauchi Consultant of: Amgen Inc., Astellas BioPharma K.K., Teijin Pharma, Mary Oates Shareholder of: Amgen Inc., Employee of: Amgen Inc., Ian Reid Consultant of: Amgen Inc., Eli Lilly, Speakers bureau: Amgen Inc., Eli Lilly, Norma Ruiz Santiago Shareholder of: Amgen Inc., Employee of: Amgen Inc., Mark Vanderkelen Employee of: UCB Pharma, Wenjing Yang Shareholder of: Amgen Inc., Employee of: Amgen Inc., Zhigang Yu Shareholder of: Amgen Inc., Employee of: Amgen Inc.

  • Romosozumab sclerostin monoclonal antibody versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy a randomised open label phase 3 trial
    The Lancet, 2017
    Co-Authors: Bente L Langdahl, Daria B. Crittenden, C Libanati, Jacques P Brown, Michael A Bolognese, Klaus Engelke, N Daizadeh, Eva Dokoupilova, Joel S Finkelstein
    Abstract:

    Summary Background Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of Romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. Methods This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of −2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous Romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 μg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. Findings Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to Romosozumab (n=218) or teriparatide (n=218). 206 patients in the Romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the Romosozumab group and −0·6% (−1·0 to −0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [ vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on Romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the Romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. Interpretation Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, Romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. Funding Amgen, Astellas, and UCB Pharma.

  • greater gains in spine and hip strength for Romosozumab compared with teriparatide in postmenopausal women with low bone mass
    Journal of Bone and Mineral Research, 2017
    Co-Authors: Tony M Keaveny, Daria B. Crittenden, Andreas Grauer, Jacques P Brown, Michael A Bolognese, Harry K Genant, Klaus Engelke, Beatriz Oliveri, Bente L Langdahl, Cesar Libanati
    Abstract:

    : Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naive postmenopausal women with low bone mass, Romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded Romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L1 vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for Romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p < 0.0001); changes in femoral strength for Romosozumab showed similar but smaller changes, increasing more with Romosozumab versus teriparatide (3.6% versus -0.7%; p = 0.027), and trending higher versus placebo (3.6% versus -0.1%; p = 0.059). Compartmental analysis revealed that the bone-strengthening effects for Romosozumab were associated with positive contributions from both the cortical and trabecular bone compartments at both the lumbar spine and hip. Taken together, these findings suggest that Romosozumab may offer patients with osteoporosis a new bone-forming therapeutic option that increases both vertebral and femoral strength within 12 months. © 2017 American Society for Bone and Mineral Research.

  • Greater Gains in Spine and Hip Strength for Romosozumab Compared With Teriparatide in Postmenopausal Women With Low Bone Mass
    Journal of Bone and Mineral Research, 2017
    Co-Authors: Tony M Keaveny, Daria B. Crittenden, Jacques P Brown, Michael A Bolognese, Harry K Genant, Klaus Engelke, Beatriz Oliveri, Bente L Langdahl, Andreas Grauer
    Abstract:

    : Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naive postmenopausal women with low bone mass, Romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded Romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L1 vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for Romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p 

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