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Paul D. Miller - One of the best experts on this subject based on the ideXlab platform.

  • long term Denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus analyses from the freedom extension cross over group
    Osteoporosis International, 2019
    Co-Authors: J P Bilezikian, Peter R Ebeling, Astrid Fahrleitnerpammer, Nigel Gilchrist, A Wang, Cjf Lin, J P Brown, Xiang Yin, Edward Franek, Paul D. Miller
    Abstract:

    Upper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with Denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites. Upper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of Denosumab treatment on upper limb fracture risk and BMD. In the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month Denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive Denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1–3, Extension years 1–3, and Extension years 4–7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4–7 (Denosumab) and FREEDOM years 1–3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all). Long-term treatment with Denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

  • differential effects of teriparatide and Denosumab on intact pth and bone formation indices ava osteoporosis study
    The Journal of Clinical Endocrinology and Metabolism, 2016
    Co-Authors: David W Dempster, Michael E Lewiecki, Paul D. Miller, David L Kendler, Jacques P Brown, Christopher Recknor, Robert R Recker, Hua Zhou, Sudhaker D Rao, Robert Lindsay
    Abstract:

    We compared effects of teriparatide and Denosumab on PTH, bone turnover markers, and bone histomorphometry in osteoporotic postmenopausal women. The findings were inconsistent with an early indirect anabolic effect of Denosumab.

  • effect of Denosumab on bone mineral density and biochemical markers of bone turnover 8 year results of a phase 2 clinical trial
    Osteoporosis International, 2013
    Co-Authors: Michael R Mcclung, Michael A Bolognese, Beiying Ding, Rachel B Wagman, Munro Peacock, E M Lewiecki, Michelle Geller, R L Weinstein, E Rockabrand, Paul D. Miller
    Abstract:

    Summary In 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.

  • a randomized placebo controlled study of the effects of Denosumab for the treatment of men with low bone mineral density
    The Journal of Clinical Endocrinology and Metabolism, 2012
    Co-Authors: Eric S Orwoll, Michael E Lewiecki, David L Kendler, Bente L Langdahl, Roland Chapurlat, E Czerwinski, Jeanyves Reginster, Christence S Teglbjaerg, Alan Kivitz, Paul D. Miller
    Abstract:

    Context: Men with low bone mineral density (BMD) were treated with Denosumab. Objective: Our objective was to investigate the effects of Denosumab compared with placebo in men with low BMD after 1 yr of treatment. Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of Denosumab 60 mg every 6 months vs. placebo in men with low BMD. Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of Denosumab therapy. After 12 months, Denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ≤ 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr os...

  • effects of Denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass
    The Journal of Clinical Endocrinology and Metabolism, 2011
    Co-Authors: Henry G Bone, Paul D. Miller, Michael A Bolognese, Chui Kin Yuen, David L Kendler, Y C Yang, Luanda Grazette, Javier San Martin, Christopher J Gallagher
    Abstract:

    Context Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. Objective The aim was to determine the effects of prior Denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. Design We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. Participants A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. Interventions Participants received placebo or 60 mg Denosumab every 6 months for 24 months, followed by 24 months off treatment. Main outcome measures We measured the percentage changes in BMD and BTM, and evaluated safety. Results Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of Denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated Denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After Denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. Conclusions In postmenopausal women with low BMD, the effects of 60 mg Denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.

Michael R Mcclung - One of the best experts on this subject based on the ideXlab platform.

  • bone mineral density after transitioning from Denosumab to alendronate
    The Journal of Clinical Endocrinology and Metabolism, 2020
    Co-Authors: David L Kendler, Peter R Ebeling, Michael R Mcclung, Shuang Huang, Arkadi Chines, Patricia Clark, Yumie Rhee, Robert Kees Stad
    Abstract:

    Context There are few studies on patients transitioning from Denosumab to bisphosphonates. Objective To investigate patient characteristics and changes in bone mineral density (BMD) after transitioning from Denosumab to alendronate. Design Randomized, open-label, 2-year crossover Denosumab Adherence Preference Satisfaction (DAPS) study (NCT00518531). Setting 25 study centers in the US and Canada. Patients Treatment-naive postmenopausal women with BMD T-scores from -2.0 to -4.0. Interventions This post hoc analysis evaluated women randomized to subcutaneous Denosumab 60 mg every 6 months in year 1 followed by once-weekly oral alendronate 70 mg in year 2. Main outcome measure A 3% BMD threshold identified participants who lost, maintained, or gained BMD in year 2 on alendronate. Results Of 126 participants randomized to Denosumab, 115 (91%) transitioned to alendronate in year 2. BMD increased by 3% to 6% with Denosumab in year 1 and by 0% to 1% with alendronate in year 2. After transitioning to alendronate, most participants maintained or increased BMD; 15.9%, 7.6%, and 21.7% lost BMD at the lumbar spine, total hip, and femoral neck, respectively. Few participants fell below their pretreatment baseline BMD value; this occurred most often in those who lost BMD in year 2. Women who lost BMD with alendronate in year 2 also showed a greater percent change in BMD with Denosumab in year 1. The BMD change in year 2 was similar regardless of baseline characteristics or adherence to oral alendronate. Conclusion Alendronate can effectively maintain the BMD gains accrued after 1 year of Denosumab in most patients, regardless of baseline characteristics.

  • vertebral fractures after discontinuation of Denosumab a post hoc analysis of the randomized placebo controlled freedom trial and its extension
    Journal of Bone and Mineral Research, 2018
    Co-Authors: Steven R Cummings, Michael R Mcclung, Ivo Valter, Serge Ferrari, Richard Eastell, Nigel Gilchrist, Jenserik Beck Jensen, Christian Roux, Ove Torring, A Wang
    Abstract:

    Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued Denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of Denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued Denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with ≥1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued Denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping Denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, Denosumab; 3.8, placebo). The vertebral fracture rate increased upon Denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing Denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue Denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.

  • femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with Denosumab
    Journal of Bone and Mineral Research, 2014
    Co-Authors: Tony M Keaveny, David L Kendler, H K Genant, Jacques P Brown, Maria Luisa Brandi, Michael R Mcclung, J R Zanchetta, Christopher Recknor, Stefan Goemaere, Richard Eastell
    Abstract:

    In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with Denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 Denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the Denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (–5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the Denosumab group (p < 0.0001) and decreased by –4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the Denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the Denosumab group. In conclusion, treatment with Denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which Denosumab reduces fracture risk for postmenopausal women with osteoporosis.

  • effect of Denosumab on bone mineral density and biochemical markers of bone turnover 8 year results of a phase 2 clinical trial
    Osteoporosis International, 2013
    Co-Authors: Michael R Mcclung, Michael A Bolognese, Beiying Ding, Rachel B Wagman, Munro Peacock, E M Lewiecki, Michelle Geller, R L Weinstein, E Rockabrand, Paul D. Miller
    Abstract:

    Summary In 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.

  • effect of Denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis
    Journal of Bone and Mineral Research, 2012
    Co-Authors: Michael R Mcclung, H G Bone, Christian Roux, Ove Torring, Steven Boonen, Salvatore Minisola, Rene Rizzoli, C L Benhamou, W F Lems, Johan Halse
    Abstract:

    Denosumab reduces the risk of new vertebral and nonvertebral fractures. Previous trials suggest that the efficacy of antiresorptives on fractures might differ by patients' characteristics, such as age, bone mineral density (BMD), and fracture history. In the FREEDOM study, 7808 women aged 60 to 90 years with osteoporosis were randomly assigned to receive subcutaneous injections of Denosumab (60 mg) or placebo every 6 months for 3 years. New vertebral and nonvertebral fractures were radiologically confirmed. Subgroup analyses described in this article were prospectively planned before study unblinding to evaluate the effect of Denosumab on new vertebral and nonvertebral fractures across various subgroups. Compared with placebo, Denosumab decreased the risk of new vertebral fractures in the overall study population over 3 years. This effect did not significantly differ for any of the nine subgroups analyzed (p > 0.09 for all potential interactions). Denosumab also reduced all nonvertebral fractures by 20% in the full study cohort over 3 years. This risk reduction was statistically significant in women with a baseline femoral neck BMD T-score ≤ −2.5 but not in those with a T-score > −2.5; in those with a body mass index (BMI) < 25 kg/m2 but not ≥ 25 kg/m2; and in those without but not with a prevalent vertebral fracture. These differential treatment effects were not explained by differences in BMD responses to Denosumab. Denosumab 60 mg administered every 6 months for 3 years in women with osteoporosis reduced the risk of new vertebral fractures to a similar degree in all subgroups. The effect of Denosumab on nonvertebral fracture risk differed by femoral neck BMD, BMI, and prevalent vertebral fracture at baseline. © 2012 American Society for Bone and Mineral Research

Olivier Lamy - One of the best experts on this subject based on the ideXlab platform.

  • clinical features of 24 patients with rebound associated vertebral fractures after Denosumab discontinuation systematic review and additional cases
    Journal of Bone and Mineral Research, 2017
    Co-Authors: Athanasios D Anastasilakis, Berengere Aubryrozier, Stergios A Polyzos, Polyzois Makras, Stella Kaouri, Olivier Lamy
    Abstract:

    We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after Denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty-four postmenopausal women with vertebral fracture(s) after Denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last Denosumab injection. Eighty-three percent of the patients were treatment naive, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut-off of 2 years, those with ≤2 years of Denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after Denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit Denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients. © 2017 American Society for Bone and Mineral Research.

  • severe rebound associated vertebral fractures after Denosumab discontinuation 9 clinical cases report
    The Journal of Clinical Endocrinology and Metabolism, 2017
    Co-Authors: Olivier Lamy, Didier Hans, Elena Gonzalezrodriguez, Delphine Stoll, Berengere Aubryrozier
    Abstract:

    Context Denosumab inhibits bone resorption, increases bone mineral density, and reduces fracture risk. Denosumab was approved for the treatment of osteoporosis and the prevention of bone loss in some oncological situations. Denosumab discontinuation is associated with a severe bone turnover rebound (BTR) and a rapid loss of bone mineral density. The clinical consequences of the BTR observed after Denosumab discontinuation are not known. Cases description We report 9 women who presented 50 rebound-associated vertebral fractures (RAVFs) after Denosumab discontinuation. A broad biological and radiological assessment excluded other causes than osteoporosis. These 9 cases are unusual and disturbing for several reasons. First, all vertebral fractures (VFs) were spontaneous, and most patients had a high number of VFs (mean = 5.5) in a short period of time. Second, the fracture risk was low for most of these women. Third, their VFs occurred rapidly after last Denosumab injection (9-16 months). Fourth, vertebroplasty was associated with a high number of new VFs. All the observed VFs seem to be related to Denosumab discontinuation and unlikely to the underlying osteoporosis or osteopenia. We hypothesize that the severe BTR is involved in microdamage accumulation in trabecular bone and thus promotes VFs. Conclusion Studies are urgently needed to determine 1) the pathophysiological processes involved, 2) the clinical profile of patients at risk for RAVFs, and 3) the management and/or treatment regimens after Denosumab discontinuation. Health authorities, physicians, and patients must be aware of this RAVF risk. Denosumab injections must be scrupulously done every 6 months but not indefinitely.

  • severe spontaneous vertebral fractures after Denosumab discontinuation three case reports
    Osteoporosis International, 2016
    Co-Authors: Berengere Aubryrozier, Elena Gonzalezrodriguez, Delphine Stoll, Olivier Lamy
    Abstract:

    Osteoporosis treatments are usually given for a limited period of time in order to balance benefits and risks. We report three cases of postmenopausal women without any previous fragility fracture who presented severe spontaneous vertebral fractures after Denosumab discontinuation. We think that the occurrence of these fractures could be explained by the severe rebound effect observed after Denosumab discontinuation and that a consensus regarding the end of treatment with Denosumab has to be defined.

David L Kendler - One of the best experts on this subject based on the ideXlab platform.

  • favorable skeletal benefit risk of long term Denosumab therapy a virtual twin analysis of fractures prevented relative to skeletal safety events observed
    Bone, 2020
    Co-Authors: Serge Ferrari, Daria B. Crittenden, Michael E Lewiecki, David L Kendler, Peter W Butler, Nicola Napoli, Shuang Huang, Nicola Pannacciulli, Ethel S Siris
    Abstract:

    Abstract Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events—atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label Denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of Denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with Denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term Denosumab group. Estimated virtual-placebo and observed long-term Denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term Denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, Denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791 , NCT00523341 .

  • bone mineral density after transitioning from Denosumab to alendronate
    The Journal of Clinical Endocrinology and Metabolism, 2020
    Co-Authors: David L Kendler, Peter R Ebeling, Michael R Mcclung, Shuang Huang, Arkadi Chines, Patricia Clark, Yumie Rhee, Robert Kees Stad
    Abstract:

    Context There are few studies on patients transitioning from Denosumab to bisphosphonates. Objective To investigate patient characteristics and changes in bone mineral density (BMD) after transitioning from Denosumab to alendronate. Design Randomized, open-label, 2-year crossover Denosumab Adherence Preference Satisfaction (DAPS) study (NCT00518531). Setting 25 study centers in the US and Canada. Patients Treatment-naive postmenopausal women with BMD T-scores from -2.0 to -4.0. Interventions This post hoc analysis evaluated women randomized to subcutaneous Denosumab 60 mg every 6 months in year 1 followed by once-weekly oral alendronate 70 mg in year 2. Main outcome measure A 3% BMD threshold identified participants who lost, maintained, or gained BMD in year 2 on alendronate. Results Of 126 participants randomized to Denosumab, 115 (91%) transitioned to alendronate in year 2. BMD increased by 3% to 6% with Denosumab in year 1 and by 0% to 1% with alendronate in year 2. After transitioning to alendronate, most participants maintained or increased BMD; 15.9%, 7.6%, and 21.7% lost BMD at the lumbar spine, total hip, and femoral neck, respectively. Few participants fell below their pretreatment baseline BMD value; this occurred most often in those who lost BMD in year 2. Women who lost BMD with alendronate in year 2 also showed a greater percent change in BMD with Denosumab in year 1. The BMD change in year 2 was similar regardless of baseline characteristics or adherence to oral alendronate. Conclusion Alendronate can effectively maintain the BMD gains accrued after 1 year of Denosumab in most patients, regardless of baseline characteristics.

  • differential effects of teriparatide and Denosumab on intact pth and bone formation indices ava osteoporosis study
    The Journal of Clinical Endocrinology and Metabolism, 2016
    Co-Authors: David W Dempster, Michael E Lewiecki, Paul D. Miller, David L Kendler, Jacques P Brown, Christopher Recknor, Robert R Recker, Hua Zhou, Sudhaker D Rao, Robert Lindsay
    Abstract:

    We compared effects of teriparatide and Denosumab on PTH, bone turnover markers, and bone histomorphometry in osteoporotic postmenopausal women. The findings were inconsistent with an early indirect anabolic effect of Denosumab.

  • further reductions in nonvertebral fracture rate with long term Denosumab treatment in the freedom open label extension and influence of hip bone mineral density after 3 years
    Osteoporosis International, 2015
    Co-Authors: Serge Ferrari, Jonathan D Adachi, David L Kendler, Ove Torring, Kurt Lippuner, C Zapalowski, P D Miller, J Y Reginster, N Daizadeh, A Wang
    Abstract:

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

  • femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with Denosumab
    Journal of Bone and Mineral Research, 2014
    Co-Authors: Tony M Keaveny, David L Kendler, H K Genant, Jacques P Brown, Maria Luisa Brandi, Michael R Mcclung, J R Zanchetta, Christopher Recknor, Stefan Goemaere, Richard Eastell
    Abstract:

    In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with Denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 Denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the Denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (–5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the Denosumab group (p < 0.0001) and decreased by –4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the Denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the Denosumab group. In conclusion, treatment with Denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which Denosumab reduces fracture risk for postmenopausal women with osteoporosis.

A Wang - One of the best experts on this subject based on the ideXlab platform.

  • long term Denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus analyses from the freedom extension cross over group
    Osteoporosis International, 2019
    Co-Authors: J P Bilezikian, Peter R Ebeling, Astrid Fahrleitnerpammer, Nigel Gilchrist, A Wang, Cjf Lin, J P Brown, Xiang Yin, Edward Franek, Paul D. Miller
    Abstract:

    Upper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with Denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites. Upper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of Denosumab treatment on upper limb fracture risk and BMD. In the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month Denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive Denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1–3, Extension years 1–3, and Extension years 4–7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4–7 (Denosumab) and FREEDOM years 1–3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all). Long-term treatment with Denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

  • vertebral fractures after discontinuation of Denosumab a post hoc analysis of the randomized placebo controlled freedom trial and its extension
    Journal of Bone and Mineral Research, 2018
    Co-Authors: Steven R Cummings, Michael R Mcclung, Ivo Valter, Serge Ferrari, Richard Eastell, Nigel Gilchrist, Jenserik Beck Jensen, Christian Roux, Ove Torring, A Wang
    Abstract:

    Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued Denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of Denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued Denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with ≥1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued Denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping Denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, Denosumab; 3.8, placebo). The vertebral fracture rate increased upon Denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing Denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue Denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.

  • further reductions in nonvertebral fracture rate with long term Denosumab treatment in the freedom open label extension and influence of hip bone mineral density after 3 years
    Osteoporosis International, 2015
    Co-Authors: Serge Ferrari, Jonathan D Adachi, David L Kendler, Ove Torring, Kurt Lippuner, C Zapalowski, P D Miller, J Y Reginster, N Daizadeh, A Wang
    Abstract:

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

  • Denosumab for prevention of fractures in postmenopausal women with osteoporosis
    The New England Journal of Medicine, 2009
    Co-Authors: Steven R Cummings, Javier San Martin, Pierre D Delmas, Matthew Austin, R Eastell, Michael R Mcclung, Ian R Reid, Ethel S Siris, Holly B Zoog, A Wang
    Abstract:

    Methods We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of Denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. Results As compared with placebo, Denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the Denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001) — a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the Denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P = 0.04) — a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the Denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) — a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of Denosumab. Conclusions Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)