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A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.

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 ?-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 ?-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and ?-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.

SUBMITTER: McClung MR

PROVIDER: S-EPMC7560921 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.

McClung M R MR Bolognese M A MA Brown J P JP Reginster J-Y JY Langdahl B L BL Maddox J J Shi Y Y Rojeski M M Meisner P D PD Grauer A A

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20200704 11

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.<h4>Introduction</h4>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 treatmen ...[more]

PMID: 32623487

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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.IntroductionIn 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.MethodsIn 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).ResultsOf 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.ConclusionsAfter 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, 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.PurposeIn 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.MethodsPostmenopausal 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.ResultsOf 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.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.

Project description:Bone mineral density (BMD) has been linked to mortality, but little is known about the independent contribution of each endosteal bone compartment and also the rate of bone loss to risk of mortality. We examined the relationships between (1) baseline trabecular and cortical volumetric BMD (vBMD) at the proximal femur, and (2) the rate of trabecular and cortical bone loss and all-cause mortality in older adults from the AGES-Reykjavik study. The analysis of trabecular and cortical vBMD and mortality was based on the baseline cohort of 4654 participants (aged ≥66 years) with a median follow-up of 9.4 years; the association between rate of bone loss and mortality was based on 2653 participants with bone loss data (median follow-up of 5.6 years). Analyses employed multivariable Cox-proportional models to estimate hazard ratios (HRs) with time-varying fracture status; trabecular and cortical variables were included together in all models. Adjusted for important confounders, Cox models showed that participants in the lowest quartile of trabecular vBMD had an increased risk of mortality compared to participants in other quartiles (HR = 1.12; 95% confidence interval (CI), 1.01 to 1.25); baseline cortical vBMD was not related to mortality (HR = 1.08; 95% CI, 0.97 to 1.20). After adjustment for time-dependent fracture status, results were attenuated and not statistically significant. A faster loss (quartile 1 versus quartiles 2-4) in both trabecular and cortical bone was associated with higher mortality risk (HR = 1.37 and 1.33, respectively); these associations were independent of major potential confounders including time-dependent incident fractures (HR = 1.32 and 1.34, respectively). Overall, data suggest that faster bone losses over time in both the trabecular and cortical bone compartments are associated with mortality risk and that measurements of change in bone health may be more informative than single-point measurements in explaining mortality differences in older adults. © 2017 American Society for Bone and Mineral Research.

Project description:This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.IntroductionIn Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies.MethodsThis multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients.ResultsNinety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level.ConclusionPrior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.

Project description:Abstract Despite clinical strides in the treatment of osteoporosis in several diverse medical conditions, the ability to maintain bone has proven to be exceedingly difficult in individuals with severe immobilization. Fifty to 60% of bone mineral density (BMD) at the epiphyseal and metaphyseal regions of the long-bones of the lower extremities may be lost over the first couple of years after spinal cord injury (SCI). Once a large amount of bone has been lost, it would be challenging to restore BMD, trabecular architectural integrity, and mechanical strength to provide protection against long-bone fractures of the lower extremities. Persons with neurologically complete forms of SCI have marked loss of BMD of the lower extremities, predisposing to fracture, especially at the knee. Denosumab, a commercially available human monoclonal antibody of the IgG2 immunoglobulin isotype with a high affinity and specificity for binding RANKL to antagonize its action, may provide an immunopharmacological solution to the rapid progressive deterioration of sublesional bone after SCI. Twenty-six patients with motor-complete SCI [International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) grade A and B] were randomized to receive denosumab or placebo at baseline (BL), 6, and 12 months. Ten participants in the denosumab group and 8 participants in the placebo group completed the 18-month clinical trial [ClinicalTrials.gov (NCT01983475)]. Dual energy x-ray absorptiometry (DXA; Lunar Prodigy Advance, all software version 12.20.023; EnCORE, GE Medical Systems, Madison, WI) and peripheral quantitative computed tomography (pQCT; Stratec XCT 3000; STIM designs, Carmel, CA) imaging were performed. Within group paired analysis revealed a significant decrease for areal BMD (aBMD) from BL in the placebo group that started at month 3 for the distal femoral epiphysis (DFE), distal femoral metaphysis (DFM), and total hip (TH) and at month 6 for the femoral neck (FN), and at month 12 for the proximal tibial epiphysis (PTE); the loss in aBMD progressed to 18 months for all the skeletal regions of interest (ROI). At 18 months, the percent change at the ROI for the denosumab vs. placebo groups were: DFE (1.1% ± 7.5 vs. -30.0% ± 11.9, respectively, p<0.001 and p<0.001), DFM (1.2% ± 6.4 vs. -17.2% ± 14.2, p<0.01), TH (3.3% ± 8.7 vs. -25.6% ± 7.6, p < 0.001), and PTE (-1.7% ± 8.2 vs. -24.1% ± 12.3, p<0.001). At 18 months, pQCT at the 4% tibial region confirmed the DXA findings at proximal tibial; at the 38% tibial region, a trend toward loss of total volumetric BMD (vBMD) was observed (-0.7% ± 4.5 vs. -16.9% ± 20.0, p<0.09), but cortical vBMD was similar between the denosumab and placebo groups, suggesting trabecular loss at the tibial shaft. In summary, the findings suggest that denosumab, if treatment is initiated within 3 months of acute SCI, appears to be an efficacious approach to maintain BMD at the knee and hip regions.

Project description:Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a -0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (-4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dataset Information

A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.

Publications

A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.

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