Years Of Denosumab Research Articles

OR13-06 Romosozumab After Denosumab Improves Lumbar Spine Bone Mineral Density And Microarchitecture Greater Than Denosumab Continuation In Postmenopausal Women

Abstract Disclosure: N. Hong: None. S. Shin: None. H. Kim: None. Y. Rhee: None. Transitioning to romosozumab from antiresorptives can be an effective strategy to improve bone strength. A phase 2 trial and a few observational studies showed improvement of lumbar spine bone mineral density (BMD) with maintained hip bone density by romosozumab after denosumab. However, whether transition to romosozumab after denosumab is associated with greater improvement in BMD and microarchitecture compared to denosumab continuation remains unclear. In this propensity score-matched cohort study, we analyzed data from postmenopausal women who initiated denosumab between 2017 and 2020 (at least two injections; n=696). Individuals who were transited to 12 months of romosozumab after denosumab (n=105) were 1:1 matched to those who continued denosumab (n=591) by propensity score using age (69 years), body mass index, BMD, and numbers of denosumab injection at the time of transition, BMD improvement during denosumab treatment, prior fracture and bisphosphonate use (n=93 for each; denosumab-romosozumab [DR] and denosumab-denosumab [DD]). BMD gain by denosumab in DR and DD groups from denosumab initiation to transition time (to romosozumab or denosumab continuation; median 4 times [range 2 to 8] of denosumab injection) was +4.6% and +2.4% in the lumbar spine (LS, T-score −3.4 to −3.1) and total hip (TH, T-score −2.5 to −2.4), without statistical difference. DR group showed greater LSBMD gain compared to the DD (+7.0% vs. +2.5%, P<0.001) during 12 months after the transition time, yielding greater net LSBMD gain in DR (median 2 years of denosumab followed by 1-year romosozumab) compared to DD (median 3 years of denosumab; +11.6% vs. +7.0%, P<0.001). Differences in LSBMD gain between DR and DD groups remained robust (adjusted difference +4.7% point, P<0.001) after adjustment for covariates. Hip BMD changes did not differ between DR and DD (DR vs. DD; FN, +1.3% vs. +2.0%, p=0.409; TH, -0.9% vs. +0.2%, P=0.132). DR group showed significant improvement in the trabecular bone score during romosozumab use (1.288 to 1.311, p=0.005), whereas denosumab continuation in the DD group did not (1.297 to 1.309, p=0.103). During 12 months, one incident morphometric vertebral fracture (grade 1) and one nonvertebral fracture (patella) were observed in DD, whereas one ankle fracture was observed in the DR group. In summary, romosozumab after denosumab improved lumbar spine BMD and microarchitecture greater than denosumab continuation, with the maintenance of hip BMD. Presentation: Friday, June 16, 2023

Long-term effect of denosumab on bone microarchitecture as assessed by tissue thickness–adjusted trabecular bone score in postmenopausal women with osteoporosis: results from FREEDOM and its open-label extension

SummaryIn postmenopausal women with osteoporosis, up to 10 years of denosumab treatment significantly and continuously improved bone microarchitecture assessed by tissue thickness–adjusted trabecular bone score, independently of bone mineral density. Long-term denosumab treatment decreased the number of high fracture-risk patients and shifted more patients to lower fracture-risk categories.PurposeTo investigate the long-term effect of denosumab on bone microarchitecture assessed by tissue thickness–adjusted trabecular bone score (TBSTT) in post-hoc subgroup analysis of FREEDOM and open-label extension (OLE).MethodsPostmenopausal women with lumbar spine (LS) or total hip BMD T-score <−2.5 and ≥−4.0 who completed the FREEDOM DXA substudy and continued in OLE were included. Patients received either denosumab 60 mg subcutaneously every 6 months for 3 years and same-dose open-label denosumab for 7 years (long-term denosumab; n=150) or placebo for 3 years and open-label denosumab for 7 years (crossover denosumab; n=129). BMD and TBSTT were assessed on LS DXA scans at FREEDOM baseline, month 1, and years 1–6, 8, and 10.ResultsIn long-term denosumab group, continued increases from baseline to years 4, 5, 6, 8, and 10 in BMD (11.6%, 13.7%, 15.5%, 18.5%, and 22.4%) and TBSTT (3.2%, 2.9%, 4.1%, 3.6%, and 4.7%) were observed (all P < 0.0001). Long-term denosumab treatment decreased the proportion of patients at high fracture-risk (according to TBSTT and BMD T-score) from baseline up to year 10 (93.7 to 40.4%), resulting in increases in the proportions at medium-risk (6.3 to 53.9%) and low-risk (0 to 5.7%) (P < 0.0001). Similar responses were observed in crossover denosumab group. Changes in BMD and TBSTT were poorly correlated during denosumab treatment.ConclusionIn postmenopausal women with osteoporosis, up to 10 years of denosumab significantly and continuously improved bone microarchitecture assessed by TBSTT, independently of BMD, and shifted more patients to lower fracture-risk categories.Graphical

Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: Observations in a real-world setting.

The rebound effect after denosumab discontinuation is lessened with subsequent zoledronate therapy. However, it is unclear whether this mitigation is sufficient after long-term denosumab treatment. This retrospective observational study analysed bone mineral density (BMD) and bone turnover marker (BTM) changes after denosumab therapy according to treatment duration and subsequent zoledronate regimen. We measured the outcomes of 282 women with postmenopausal osteoporosis who discontinued denosumab and received zoledronate 6months later. In patients with longer denosumab therapy (≥5years), BTMs were measured every 3months and a second zoledronate infusion was administered if BTM levels increased by ≥2-fold. The BMD of all women was measured before denosumab therapy, at the last injection and 1 to 2years after the first zoledronate. Bone loss after switching from denosumab to zoledronate was higher in patients with 10±2 denosumab injections (n=84) compared to 5±2 injections (n=144, p<0.001 for lumbar spine and femoral neck), but there was no further increase with treatment durations of ≥15±2 injections (n=54, p=0.35 and p=0.20, respectively). BTMs in patients with ≥10 denosumab injections were elevated 6months after zoledronate in some patients, but not all. Twenty-four women received a second zoledronate dose 6months after the first one. BTMs in these patients were subsequently lower, but bone loss at both the lumbar spine and hip was comparable to that in patients with only one zoledronate dose (p=0.37 for lumbar spine and p=0.97 for femoral neck). Rebound-associated bone loss reached a plateau after denosumab treatment durations of 4-6years, irrespective of the frequency of subsequent zoledronate therapy.

Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis.

ContextDenosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis.ObjectiveDetermine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics.Design and SettingInternational, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension.PatientsPostmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points.InterventionsFREEDOM subjects were randomized 1:1 to subcutaneous denosumab 60 mg or placebo every 6 months for 3 years. Long-term extension subjects continued receiving denosumab, open-label, for 7 additional years.OutcomesBone histology, histomorphometry, matrix mineralization.ResultsTen-year denosumab biopsies showed normal histology. Bone histomorphometry indicated normal bone structure and reduced bone remodeling after 10 years of denosumab, similar to levels after 2 and/or 3 and 5 years of denosumab. The degree of mineralization of bone was increased and mineralization heterogeneity was reduced in the denosumab years 2/3 group vs placebo. Changes in these mineralization variables progressed from years 2/3 to year 5 of denosumab, but not thereafter.ConclusionsDenosumab for 2/3, 5, and 10 years was associated with normal histology, low bone remodeling rate, increased matrix mineralization, and lower mineralization heterogeneity compared with placebo. These variables were unchanged from year 5 to year 10. These data, in combination with the maintenance of low fracture rates for up to 10 years as previously reported with denosumab therapy, suggest that strong, prolonged remodeling inhibition does not impair bone strength.

Bone Mineral Density Changes After 1 Year of Denosumab Discontinuation in Postmenopausal Women with Long-Term Denosumab Treatment for Osteoporosis.

The aim of the present study was to document the changes in bone mineral density (BMD) 1 year after denosumab loss-of-effect following long-term treatment with subcutaneous denosumab 60mg Q6M during 7 or 10years and in the absence of any treatment with a bone active substance. All postmenopausal women with osteoporosis who participated to the randomized placebo-controlled FREEDOM core trial and its open-label extension at the University Hospital of Bern, Switzerland, and who accepted to undergo off-treatment follow-up during 1 year after discontinuation, were included (N = 12). After 10years of denosumab, mean lumbar spine (LS) BMD had increased by 21.2% vs. baseline. One year after discontinuation LS BMD had decreased by - 9.1% vs. Year 10, resulting in a net gain of 10.2% vs. baseline. At total hip (TH) and femoral neck (FN), BMD had increased by 8.3 and 8.1% in Year 10 vs. baseline, respectively. 1 Year after discontinuation, BMD had decreased by - 12.7 and - 11.0% vs. Year 10, respectively, corresponding to net BMD losses of - 5.5 and - 3.8% vs. baseline, respectively. Similar albeit less pronounced changes were observed in those treated with denosumab during 7years. Stopping denosumab after long-term exposure resulted in BMD losses of large order of magnitude at all measured sites, suggesting that treatment duration may predict the rate and amount of bone lost.

10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension

Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Amgen.

Relationship between total hip (TH) BMD T-score and incidence of nonvertebral fracture (NVFX) with up to 10 years of Denosumab (Dmab) treatment

Relationship between total hip (TH) BMD T-score and incidence of nonvertebral fracture (NVFX) with up to 10 years of Denosumab (Dmab) treatment

Two Years of Denosumab and Teriparatide Administration in Postmenopausal Women With Osteoporosis (The DATA Extension Study): A Randomized Controlled Trial

Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone. The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent. Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 μg daily), denosumab (60 mg every 6 months), or both medications for 24 months. Participants were 94 postmenopausal women with osteoporosis. Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured. At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy. Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.

The Effect of Three or Six Years of Denosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the FREEDOM Extension

Context:The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years.Objective:The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure.Design, Setting, and Participants:This was a multicenter, international, open-label study of 4550 women.Intervention:Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover).Main Outcome Measures:Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported.Results:Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture.Conclusion:Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

OP0251 Bone Histology and Histomorphometry: Effects of 5 Years of Denosumab in the Freedom Study Extension

BackgroundDenosumab (DMAb) reduces bone turnover in transiliac crest bone biopsies, which is reversible on treatment cessation (Reid JBMR 2010; Brown JBMR 2011). Long-term DMAb treatment sustains reduction in bone turnover...

Bone histology and histomorphometry: effects of 5 years of denosumab in the FREEDOM Extension

Bone histology and histomorphometry: effects of 5 years of denosumab in the FREEDOM Extension

Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial

SummaryIn a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab treatment was well tolerated throughout the 8-year study.IntroductionThe purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study.MethodsIn the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab.ResultsOf the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (N = 88) and total hip (N = 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort.ConclusionContinued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.

Denosumab: Anti-RANKL antibody

Denosumab (anti-receptor activator of nuclear factor-kappaB ligand antibody) is a novel agent, a fully human monoclonal antibody that inhibits osteoclastic-medicated bone resorption by binding to osteoblast-produced RANKL. By reducing RANKL binding to the osteoclast receptor RANK, bone resorption and turnover decrease. In phase 2 dose-ranging studies, denosumab had a rapid onset and offset effect. Also, in patients who had received 2 years of denosumab and were discontinued for the third year, rechallenge with denosumab during the fourth year demonstrated a return of responsiveness to denosumab that mimicked the initial treatment. Phase 3 pivotal fracture data were recently presented with positive outcome data; denosumab (60 mg subcutaneously every 6 months) significantly reduced vertebral, nonvertebral, and hip fracture risk compared with placebo, and had an excellent safety profile through 3 years of use. Denosumab will offer a novel approach to managing postmenopausal osteoporosis, one that should be associated with a high adherence rate and global fracture risk reduction.