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Gary Hattersley - One of the best experts on this subject based on the ideXlab platform.
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forearm bone mineral density and fracture incidence in postmenopausal women with osteoporosis results from the activextend phase 3 trial
Osteoporosis International, 2021Co-Authors: Nelson B Watts, Gary Hattersley, Bruce H Mitlak, Y Wang, Robin K Dore, S. Baim, T.d. Rozental, M.s. LeboffAbstract:Abaloparatide increased ultradistal radius bone mineral density (BMD) in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. Over the subsequent 24 months in ACTIVExtend, ultradistal radius BMD gains were maintained with alendronate. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. Abaloparatide (ABL) increased femoral neck, total hip, and lumbar spine bone mineral density (BMD) in postmenopausal women with osteoporosis and decreased the risk of vertebral and nonvertebral fractures in ACTIVE. Effects on fracture risk and BMD were maintained subsequently with alendronate (ALN) in ACTIVExtend. In a prespecified subanalysis of ACTIVE, ABL also increased BMD at the ultradistal radius. Our objective was to determine the efficacy of ABL followed by ALN vs placebo (PBO) followed by ALN on forearm BMD and fracture risk over 43 months in ACTIVExtend. Ultradistal and 1/3 radius BMD (ACTIVE baseline to month 43) were measured (ABL/ALN, n = 213; PBO/ALN, n = 233). Wrist fracture rates were estimated for the ACTIVExtend intent-to-treat population (ABL/ALN, n = 558; PBO/ALN, n = 581) by Kaplan-Meier (KM) method. At cumulative month 25, mean increase from ACTIVE baseline in ultradistal radius BMD was 1.1% (standard error, 0.49%) with ABL/ALN vs − 0.8% (0.43%) with PBO/ALN (P < 0.01). BMD increases with ABL were maintained with ALN through month 43 in ACTIVExtend. BMD decreases at the 1/3 radius in ACTIVE (similar with ABL and PBO) were maintained through 24 months of ALN treatment in ACTIVExtend. Wrist fractures over 43 months occurred in 15 women with ABL/ALN (KM estimate, 2.8%) and 20 with PBO/ALN (KM estimate, 3.6%) (HR = 0.77, 95% CI 0.39, 1.50; P = not significant). Ultradistal radius BMD gains following treatment with ABL in ACTIVE were maintained over 24 months of ALN treatment in ACTIVExtend. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. ClinicalTrials.gov : NCT01657162 submitted July 31, 2012
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Abaloparatide in postmenopausal women with osteoporosis and type 2 diabetes a post hoc analysis of the active study
JBMR Plus, 2020Co-Authors: Ruban Dhaliwal, Gary Hattersley, Bruce H Mitlak, Paul D. Miller, Yamei Wang, Lorraine A Fitzpatrick, Didier Hans, Ann V Schwartz, Robert G JosseAbstract:Type 2 diabetes mellitus (T2DM) increases fracture risk despite normal or increased BMD. Abaloparatide reduces fracture risk in patients with postmenopausal osteoporosis (PMO); however, its efficacy in women with T2DM is unknown. This post hoc analysis evaluated the efficacy and safety of Abaloparatide in patients with T2DM. The analysis included patients with T2DM from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), a phase 3, double-blind, randomized, placebo- and active-controlled trial. In ACTIVE, participants were randomized 1:1:1 to daily s.c. injections of placebo, Abaloparatide (80 μg), or open-label teriparatide (20 μg) for 18 months. A total of 198 women with PMO and T2DM from 21 centers in 10 countries were identified from ACTIVE through review of their medical records. The main outcomes measured included effect of Abaloparatide versus placebo on BMD and trabecular bone score (TBS), with secondary outcomes of fracture risk and safety, in patients from ACTIVE with T2DM. Significant (p < 0.001) improvements in BMD at total hip (mean change 3.0% versus -0.4%), femoral neck (2.6% versus -0.2%), and lumbar spine (8.9% versus 1.3%) and TBS at lumbar spine (3.72% versus -0.56%) were observed with Abaloparatide versus placebo at 18 months. Fracture events were fewer with Abaloparatide treatment in patients with T2DM, and differences were not significant between groups except nonvertebral fractures in the Abaloparatide versus placebo groups (p = 0.04). Safety was consistent with the ACTIVE population. In conclusion, in women with PMO and T2DM, Abaloparatide treatment resulted in significant improvements in BMD and TBS versus placebo, consistent with the overall ACTIVE population © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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effect of Abaloparatide vs alendronate on fracture risk reduction in postmenopausal women with osteoporosis
The Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Benjamin Z Leder, Gary Hattersley, Bruce H Mitlak, Richard S BockmanAbstract:Context The ACTIVE study demonstrated the antifracture efficacy of Abaloparatide in postmenopausal women with osteoporosis. ACTIVExtend demonstrated sustained fracture risk reduction with alendronate in Abaloparatide-treated participants from ACTIVE. A direct comparison of the efficacy of Abaloparatide and antiresorptive therapies has not been performed. Objective The objective of this analysis is to compare the antifracture efficacy of Abaloparatide in ACTIVE with that of alendronate in ACTIVExtend. Design In this post hoc analysis, the rate of new vertebral fractures for women in ACTIVExtend (N = 1139) was calculated based on baseline and endpoint radiographs for placebo or Abaloparatide in ACTIVE and alendronate in ACTIVExtend. Vertebral fracture rates between Abaloparatide and alendronate were compared in a Poisson regression model. Fracture rates for nonvertebral and clinical fractures were compared based on a Poisson model during 18 months of Abaloparatide or placebo treatment in ACTIVE and 18 months of alendronate treatment in ACTIVExtend. Results The vertebral fracture rate was lower during Abaloparatide treatment in ACTIVE (0.47 fractures/100 patient-years) than alendronate treatment in ACTIVExtend (1.66 fractures/100 patient-years) (relative risk reduction 71%; P = .027). Although the comparisons did not meet statistical significance, after switching from placebo (ACTIVE) to alendronate (ACTIVExtend), the rate of new vertebral fractures decreased from 2.49 to 1.66 fractures per 100 patient-years, and after switching from Abaloparatide to alendronate from 0.47 to 0.19 fractures per 100 patient-years. The rates of nonvertebral fractures and clinical fractures were not significantly different. Conclusion Initial treatment with Abaloparatide may result in greater vertebral fracture reduction compared with alendronate in postmenopausal women with osteoporosis.
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fracture and bone mineral density response by baseline risk in patients treated with Abaloparatide followed by alendronate results from the phase 3 activextend trial
Journal of Bone and Mineral Research, 2019Co-Authors: Benjamin Z Leder, Gary Hattersley, Carol Zapalowski, Nancy E Lane, Andrea J Singer, Robin K DoreAbstract:In the randomized, placebo-controlled, double-blind phase 3 ACTIVE study (NCT01343004), 18 months of Abaloparatide 80 μg daily (subcutaneous injection) in postmenopausal women at risk of osteoporotic fracture significantly reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and significantly increased bone mineral density (BMD) versus placebo regardless of baseline risk factors. Women from the Abaloparatide and placebo groups who completed ACTIVE were eligible for ACTIVExtend (NCT01657162), in which all enrollees received sequential, open-label monotherapy with alendronate 70 mg once weekly for up to 24 months. This prespecified analysis evaluated whether fracture risk reductions and bone mineral density (BMD) gains associated with Abaloparatide during ACTIVE persisted through the full 43-month ACTIVE-ACTIVExtend study period in nine prespecified baseline risk subgroups. Baseline risk subgroups included BMD T-score at the lumbar spine, total hip, and femoral neck (≤ - 2.5 versus > - 2.5 and ≤ -3.0 versus > - 3.0), history of nonvertebral fracture (yes/no), prevalent vertebral fracture (yes/no), and age (<65 versus 65 to <75 versus ≥75 years). Forest plots display treatment effect. Treatment-by-subgroup interactions were tested using the Breslow-Day test, Cox proportional hazards model, and ANCOVA model. After the combined ACTIVE-ACTIVExtend study period, reductions in relative risk for new vertebral, nonvertebral, clinical, and major osteoporotic fractures were greater among patients in the Abaloparatide/alendronate group than among those in the placebo/alendronate group across all nine baseline risk subgroups. BMD gains at the lumbar spine, total hip, and femoral neck were greater in the Abaloparatide/alendronate group versus the placebo/alendronate group. No clinically meaningful interaction between treatment assignment and any baseline risk variable was observed. The sequence of Abaloparatide for 18 months followed by alendronate for up to 24 months appears to be an effective treatment option for a wide range of postmenopausal women at risk for osteoporotic fractures. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
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Abaloparatide in patients with mild or moderate renal impairment results from the active phase 3 trial
Current Medical Research and Opinion, 2019Co-Authors: John P Bilezikian, Gary Hattersley, Bruce H Mitlak, Paul D. Miller, Lorraine A Fitzpatrick, C Dabrowski, Socrates E PapapoulosAbstract:AbstractObjective: To evaluate, post hoc, the efficacy and safety of Abaloparatide by degree of renal impairment.Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator...
Lorraine A Fitzpatrick - One of the best experts on this subject based on the ideXlab platform.
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Abaloparatide an anabolic treatment to reduce fracture risk in postmenopausal women with osteoporosis
Current Medical Research and Opinion, 2020Co-Authors: Paul D. Miller, Bruce H Mitlak, Felicia Cosman, Lorraine A Fitzpatrick, E V Mccloskey, John P Bilezikian, H G BoneAbstract:Fractures due to osteoporosis represent a serious burden on patients and healthcare systems. The objective of this review is to provide an overview of the anabolic agent Abaloparatide (ABL) for the...
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Abaloparatide followed by alendronate in women 80 years with osteoporosis post hoc analysis of activextend
Menopause, 2020Co-Authors: Susan L Greenspan, Bruce H Mitlak, Felicia Cosman, Yamei Wang, Lorraine A Fitzpatrick, Nicholas C Harvey, Chad L Deal, Michael R McclungAbstract:OBJECTIVE Fracture risk increases with age, but few studies focus on persons ≥80 years. In the ACTIVE trial, treatment with Abaloparatide for 18 months reduced osteoporotic fracture risk and increased bone mineral density. These effects were maintained with 24 months alendronate treatment in ACTIVExtend. We postulated that similar improvements in bone mineral density and safety would be demonstrated in women ≥80 years. METHODS Post hoc analyses of bone mineral density and fracture incidence in women with osteoporosis at high risk of fracture ≥80 years from ACTIVExtend. RESULTS In total, 56 women aged ≥80 years at ACTIVE baseline entered the ACTIVExtend study; 46 of these completed the study. Mean age was 83.3 years; other baseline characteristics were similar. At the end of ACTIVE, bone mineral density increased at all sites for Abaloparatide versus placebo. Bone mineral density increased in parallel in both groups during alendronate therapy (19 to 43 months) in ACTIVExtend. At month 43, mean percent change in bone mineral density from baseline was 17.2% Abaloparatide/alendronate versus 8.6% placebo/alendronate (P < 0.0001) at the lumbar spine, 5.3% Abaloparatide/alendronate versus 3.0% placebo/alendronate (P = 0.024) at the total hip, and 4.6% Abaloparatide/alendronate versus 3.1% placebo/alendronate (P = 0.044) at the femoral neck. Fracture incidence was low and did not differ significantly between groups. Sequential treatment with Abaloparatide followed by alendronate was well tolerated; the proportion of participants reporting adverse events was similar between groups. CONCLUSIONS Sequential treatment with Abaloparatide followed by alendronate (43 months follow-up) in this small subgroup of ACTIVExtend participants suggests Abaloparatide is well tolerated and effective in women aged ≥80 years. : Video Summary:http://links.lww.com/MENO/A618.
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Abaloparatide in postmenopausal women with osteoporosis and type 2 diabetes a post hoc analysis of the active study
JBMR Plus, 2020Co-Authors: Ruban Dhaliwal, Gary Hattersley, Bruce H Mitlak, Paul D. Miller, Yamei Wang, Lorraine A Fitzpatrick, Didier Hans, Ann V Schwartz, Robert G JosseAbstract:Type 2 diabetes mellitus (T2DM) increases fracture risk despite normal or increased BMD. Abaloparatide reduces fracture risk in patients with postmenopausal osteoporosis (PMO); however, its efficacy in women with T2DM is unknown. This post hoc analysis evaluated the efficacy and safety of Abaloparatide in patients with T2DM. The analysis included patients with T2DM from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), a phase 3, double-blind, randomized, placebo- and active-controlled trial. In ACTIVE, participants were randomized 1:1:1 to daily s.c. injections of placebo, Abaloparatide (80 μg), or open-label teriparatide (20 μg) for 18 months. A total of 198 women with PMO and T2DM from 21 centers in 10 countries were identified from ACTIVE through review of their medical records. The main outcomes measured included effect of Abaloparatide versus placebo on BMD and trabecular bone score (TBS), with secondary outcomes of fracture risk and safety, in patients from ACTIVE with T2DM. Significant (p < 0.001) improvements in BMD at total hip (mean change 3.0% versus -0.4%), femoral neck (2.6% versus -0.2%), and lumbar spine (8.9% versus 1.3%) and TBS at lumbar spine (3.72% versus -0.56%) were observed with Abaloparatide versus placebo at 18 months. Fracture events were fewer with Abaloparatide treatment in patients with T2DM, and differences were not significant between groups except nonvertebral fractures in the Abaloparatide versus placebo groups (p = 0.04). Safety was consistent with the ACTIVE population. In conclusion, in women with PMO and T2DM, Abaloparatide treatment resulted in significant improvements in BMD and TBS versus placebo, consistent with the overall ACTIVE population © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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response rates for hip femoral neck and lumbar spine bone mineral density in patients treated with Abaloparatide followed by alendronate results from phase 3 activextend
Bone reports, 2019Co-Authors: Chad L Deal, Bruce H Mitlak, Yamei Wang, Lorraine A Fitzpatrick, Paul D. MillerAbstract:Abstract Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor signaling pathway that favors the stimulation of bone formation. Here, we report a prospective, exploratory analysis of bone mineral density (BMD) response rates comparing sequential Abaloparatide/alendronate vs placebo/alendronate across the ACTIVE and ACTIVExtend studies. BMD was measured at the lumbar spine, total hip, and femoral neck from the beginning of ACTIVE to the end of ACTIVExtend (18 months of Abaloparatide or placebo followed by about 1 month for re-consent, followed by 24 months of alendronate treatment for a total of 43 months). Responders were defined as those patients who had improvements in BMD at 3 anatomic sites—the lumbar spine, total hip, and femoral neck. Three response thresholds, >0%, >3%, and >6%, were evaluated. Five hundred fifty-eight patients in the Abaloparatide/alendronate group and 581 patients in the placebo/alendronate group from ACTIVExtend were included in the analysis. At Month 43, a significantly greater proportion of those in the Abaloparatide/alendronate group compared with the placebo/alendronate group responded with BMD changes from ACTIVE baseline of >0%, >3%, and >6% at all 3 anatomic sites (p 3% threshold, 60.7% (307/506) vs 24.0% (121/505) of patients experienced BMD increases at all 3 sites in the Abaloparatide/alendronate vs placebo/alendronate groups, respectively (p 0%, >3%, and >6% at each individual anatomic site compared with the placebo/alendronate group at 43 months (p
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Abaloparatide in patients with mild or moderate renal impairment results from the active phase 3 trial
Current Medical Research and Opinion, 2019Co-Authors: John P Bilezikian, Gary Hattersley, Bruce H Mitlak, Paul D. Miller, Lorraine A Fitzpatrick, C Dabrowski, Socrates E PapapoulosAbstract:AbstractObjective: To evaluate, post hoc, the efficacy and safety of Abaloparatide by degree of renal impairment.Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator...
Paul D. Miller - One of the best experts on this subject based on the ideXlab platform.
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Phase 1b Evaluation of Abaloparatide Solid Microstructured Transdermal System (Abaloparatide-sMTS) in Postmenopausal Women with Low Bone Mineral Density
Clinical Drug Investigation, 2021Co-Authors: Paul D. Miller, Steven Troy, Richard J. Weiss, Miriam Annett, Jason Schense, Setareh A. Williams, Bruce MitlakAbstract:Osteoporosis is a serious health condition that causes more than 2 million fractures in the USA annually. Treatment options for osteoporosis include drugs that prevent bone resorption and anabolic agents that build new bone. Bone anabolic agents, such as Abaloparatide, have been shown to increase bone mineral density and reduce the risk of fracture in postmenopausal women with osteoporosis. Currently, all bone anabolic agents are delivered by subcutaneous injection. However, some patients do not like injectable treatments, which can negatively impact patients’ adherence to prescribed medication. In this study, we describe a novel mode of administration, the Abaloparatide-solid Microstructured Transdermal System (Abaloparatide-sMTS), which is applied to the thigh for 5 min and delivers Abaloparatide intradermally. The study showed that this new method delivered Abaloparatide into the blood as effectively as subcutaneous injections and demonstrated signs of activity in the body. Study participants were satisfied with Abaloparatide-sMTS and found it easy to use. The most common side effects were skin related, including redness, pain, and swelling, which resolved shortly after dosing. Background and Objective Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The Abaloparatide-solid Microstructured Transdermal System [Abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers Abaloparatide intradermally, is in development to provide an alternative method for Abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer Abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers. Methods In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50–85 years with low BMD were trained to self-administer Abaloparatide-sMTS 300 μg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to Abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety. Results All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was − 1.32, and mean lumbar spine T-score was − 1.98. On Day 1, the median time to reach maximum concentration ( T _max) for Abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration ( C _max) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC_0– t ) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale). Conclusions Subjects successfully self-administered Abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with Abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of Abaloparatide-sMTS. Trial Registration Number NCT04366726, Date of registration 04/29/2020, retrospectively registered
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phase 1b evaluation of Abaloparatide solid microstructured transdermal system Abaloparatide smts in postmenopausal women with low bone mineral density
Clinical Drug Investigation, 2021Co-Authors: Paul D. Miller, Steven Troy, Miriam Annett, Jason Schense, Setareh A. Williams, Rick Weiss, Bruce H MitlakAbstract:Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The Abaloparatide-solid Microstructured Transdermal System [Abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers Abaloparatide intradermally, is in development to provide an alternative method for Abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer Abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers. In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50–85 years with low BMD were trained to self-administer Abaloparatide-sMTS 300 μg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to Abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety. All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was − 1.32, and mean lumbar spine T-score was − 1.98. On Day 1, the median time to reach maximum concentration (Tmax) for Abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (Cmax) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0–t) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale). Subjects successfully self-administered Abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with Abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of Abaloparatide-sMTS. NCT04366726, Date of registration 04/29/2020, retrospectively registered Osteoporosis is a serious health condition that causes more than 2 million fractures in the USA annually. Treatment options for osteoporosis include drugs that prevent bone resorption and anabolic agents that build new bone. Bone anabolic agents, such as Abaloparatide, have been shown to increase bone mineral density and reduce the risk of fracture in postmenopausal women with osteoporosis. Currently, all bone anabolic agents are delivered by subcutaneous injection. However, some patients do not like injectable treatments, which can negatively impact patients’ adherence to prescribed medication. In this study, we describe a novel mode of administration, the Abaloparatide-solid Microstructured Transdermal System (Abaloparatide-sMTS), which is applied to the thigh for 5 min and delivers Abaloparatide intradermally. The study showed that this new method delivered Abaloparatide into the blood as effectively as subcutaneous injections and demonstrated signs of activity in the body. Study participants were satisfied with Abaloparatide-sMTS and found it easy to use. The most common side effects were skin related, including redness, pain, and swelling, which resolved shortly after dosing.
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early effects of Abaloparatide on bone formation and resorption indices in postmenopausal women with osteoporosis
Journal of Bone and Mineral Research, 2021Co-Authors: David W Dempster, Benjamin Z Leder, Michael S Ominsky, Paul D. Miller, Miriam Annett, Hua Zhou, Sudhaker D Rao, Chris Recknor, Bruce H MitlakAbstract:Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of Abaloparatide on indices of bone formation and to assess the effect of Abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg Abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of Abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with Abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which Abaloparatide improves bone mass and lowers fracture risk. © 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).
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Abaloparatide an anabolic treatment to reduce fracture risk in postmenopausal women with osteoporosis
Current Medical Research and Opinion, 2020Co-Authors: Paul D. Miller, Bruce H Mitlak, Felicia Cosman, Lorraine A Fitzpatrick, E V Mccloskey, John P Bilezikian, H G BoneAbstract:Fractures due to osteoporosis represent a serious burden on patients and healthcare systems. The objective of this review is to provide an overview of the anabolic agent Abaloparatide (ABL) for the...
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Abaloparatide in postmenopausal women with osteoporosis and type 2 diabetes a post hoc analysis of the active study
JBMR Plus, 2020Co-Authors: Ruban Dhaliwal, Gary Hattersley, Bruce H Mitlak, Paul D. Miller, Yamei Wang, Lorraine A Fitzpatrick, Didier Hans, Ann V Schwartz, Robert G JosseAbstract:Type 2 diabetes mellitus (T2DM) increases fracture risk despite normal or increased BMD. Abaloparatide reduces fracture risk in patients with postmenopausal osteoporosis (PMO); however, its efficacy in women with T2DM is unknown. This post hoc analysis evaluated the efficacy and safety of Abaloparatide in patients with T2DM. The analysis included patients with T2DM from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), a phase 3, double-blind, randomized, placebo- and active-controlled trial. In ACTIVE, participants were randomized 1:1:1 to daily s.c. injections of placebo, Abaloparatide (80 μg), or open-label teriparatide (20 μg) for 18 months. A total of 198 women with PMO and T2DM from 21 centers in 10 countries were identified from ACTIVE through review of their medical records. The main outcomes measured included effect of Abaloparatide versus placebo on BMD and trabecular bone score (TBS), with secondary outcomes of fracture risk and safety, in patients from ACTIVE with T2DM. Significant (p < 0.001) improvements in BMD at total hip (mean change 3.0% versus -0.4%), femoral neck (2.6% versus -0.2%), and lumbar spine (8.9% versus 1.3%) and TBS at lumbar spine (3.72% versus -0.56%) were observed with Abaloparatide versus placebo at 18 months. Fracture events were fewer with Abaloparatide treatment in patients with T2DM, and differences were not significant between groups except nonvertebral fractures in the Abaloparatide versus placebo groups (p = 0.04). Safety was consistent with the ACTIVE population. In conclusion, in women with PMO and T2DM, Abaloparatide treatment resulted in significant improvements in BMD and TBS versus placebo, consistent with the overall ACTIVE population © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Felicia Cosman - One of the best experts on this subject based on the ideXlab platform.
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teriparatide and Abaloparatide treatment for osteoporosis
2021Co-Authors: Felicia CosmanAbstract:Abstract Teriparatide (TPTD), approved in the United States in 2002, and Abaloparatide (ABL), FDA-approved in 2017, are anabolic agents that interact with the PTH1 receptor in bone to increase the rate and extent of bone formation. Some clinical differences between the compounds may relate to the relative affinities of these agents to different conformations of the receptor (RG and R0). Both agents improve bone mass and help restore bone microstructure. When administered by daily subcutaneous injection over 18–24 months, these agents reduce the incidence of both vertebral and nonvertebral fractures. The fracture risk reductions occur more rapidly and are of greater magnitude than those seen with antiresorptive agents. Therefore these anabolic medications should be considered first-line therapy for patients at very high imminent risk of fracture, such as those with recent clinical fracture, recently diagnosed radiographic vertebral fracture, or history of multiple fractures. TPTD and ABL should be followed by potent antiresorptive agents to maintain or enhance bone mass and bone strength.
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cardiovascular safety of Abaloparatide in postmenopausal women with osteoporosis analysis from the active phase 3 trial
The Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Felicia Cosman, Bruce H Mitlak, Linda R Peterson, Dwight A Towler, Yamei Wang, Steven R CummingsAbstract:Context Abaloparatide is an FDA-approved PTHrp analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. Objectives We assessed the cardiovascular safety profile of Abaloparatide. Design Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACE) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to Abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the Abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults. Results Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (SD) HR change from pre-treatment to 1 hour post treatment was 7.9 (8.5) bpm for Abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour post treatment was -2.7/-3.6 mmHg (Abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9‒1.0%). In a post hoc analysis, time-to-first incidence of MACE + HF was longer with Abaloparatide (P = 0.02 versus placebo) and teriparatide (P = 0.04 versus placebo). Conclusions Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.
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Abaloparatide an anabolic treatment to reduce fracture risk in postmenopausal women with osteoporosis
Current Medical Research and Opinion, 2020Co-Authors: Paul D. Miller, Bruce H Mitlak, Felicia Cosman, Lorraine A Fitzpatrick, E V Mccloskey, John P Bilezikian, H G BoneAbstract:Fractures due to osteoporosis represent a serious burden on patients and healthcare systems. The objective of this review is to provide an overview of the anabolic agent Abaloparatide (ABL) for the...
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Abaloparatide followed by alendronate in women 80 years with osteoporosis post hoc analysis of activextend
Menopause, 2020Co-Authors: Susan L Greenspan, Bruce H Mitlak, Felicia Cosman, Yamei Wang, Lorraine A Fitzpatrick, Nicholas C Harvey, Chad L Deal, Michael R McclungAbstract:OBJECTIVE Fracture risk increases with age, but few studies focus on persons ≥80 years. In the ACTIVE trial, treatment with Abaloparatide for 18 months reduced osteoporotic fracture risk and increased bone mineral density. These effects were maintained with 24 months alendronate treatment in ACTIVExtend. We postulated that similar improvements in bone mineral density and safety would be demonstrated in women ≥80 years. METHODS Post hoc analyses of bone mineral density and fracture incidence in women with osteoporosis at high risk of fracture ≥80 years from ACTIVExtend. RESULTS In total, 56 women aged ≥80 years at ACTIVE baseline entered the ACTIVExtend study; 46 of these completed the study. Mean age was 83.3 years; other baseline characteristics were similar. At the end of ACTIVE, bone mineral density increased at all sites for Abaloparatide versus placebo. Bone mineral density increased in parallel in both groups during alendronate therapy (19 to 43 months) in ACTIVExtend. At month 43, mean percent change in bone mineral density from baseline was 17.2% Abaloparatide/alendronate versus 8.6% placebo/alendronate (P < 0.0001) at the lumbar spine, 5.3% Abaloparatide/alendronate versus 3.0% placebo/alendronate (P = 0.024) at the total hip, and 4.6% Abaloparatide/alendronate versus 3.1% placebo/alendronate (P = 0.044) at the femoral neck. Fracture incidence was low and did not differ significantly between groups. Sequential treatment with Abaloparatide followed by alendronate was well tolerated; the proportion of participants reporting adverse events was similar between groups. CONCLUSIONS Sequential treatment with Abaloparatide followed by alendronate (43 months follow-up) in this small subgroup of ACTIVExtend participants suggests Abaloparatide is well tolerated and effective in women aged ≥80 years. : Video Summary:http://links.lww.com/MENO/A618.
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Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis
Osteoporosis International, 2019Co-Authors: Nelson B Watts, Gary Hattersley, Paul D. Miller, Gregory C Williams, Lorraine A Fitzpatrick, Y Wang, Felicia CosmanAbstract:Wrist fractures are common, contribute significantly to morbidity in women with postmenopausal osteoporosis, and occur predominantly at the ultradistal radius, a site rich in trabecular bone. This exploratory analysis of the phase 3 ACTIVE study evaluated effects of Abaloparatide versus placebo and teriparatide on forearm bone mineral density (BMD) and risk of wrist fracture. Forearm BMD was measured by dual energy X-ray absorptiometry in a subset of 982 women from ACTIVE, evenly distributed across the three treatment groups. Wrist fractures were ascertained in the total cohort (N = 2463). After 18 months, ultradistal radius BMD changes from baseline were 2.25 percentage points greater for Abaloparatide compared with placebo (95% confidence interval (CI) 1.38, 3.12, p < 0.001) and 1.54 percentage points greater for Abaloparatide compared with teriparatide (95% CI 0.64, 2.45, p < 0.001). At 18 months, 1/3 radius BMD losses (versus baseline) were similar for Abaloparatide compared with placebo (−0.42; 95% CI −1.03, 0.20; p = 0.19) but losses with teriparatide exceeded those of placebo (−1.66%; 95% CI −2.27, −1.06; p < 0.001). The decline with Abaloparatide was less than that seen with teriparatide (group difference 1.22%; 95% CI 0.57, 1.87; p < 0.001). The radius BMD findings, at both ultradistal and 1/3 sites, are consistent with the numerically lower incidence of wrist fractures observed in women treated with Abaloparatide compared with teriparatide (HR = 0.43; 95% CI 0.18, 1.03; p = 0.052) and placebo (HR = 0.49, 95% CI 0.20, 1.19, p = 0.11). Compared with teriparatide, Abaloparatide increased BMD at the ultradistal radius (primarily trabecular bone) and decreased BMD to a lesser extent at the 1/3 radius (primarily cortical bone), likely contributing to the numerically lower wrist fracture incidence observed with Abaloparatide.
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differential effects of Abaloparatide and teriparatide on hip cortical volumetric bmd by dxa based 3d modeling
Osteoporosis International, 2021Co-Authors: Renaud Winzenrieth, Y Wang, M S Ominsky, Ludovic Humbert, R J WeissAbstract:In postmenopausal osteoporotic women in ACTIVE, Abaloparatide reduced fracture risk and increased areal bone mineral density (BMD) more than teriparatide at the hip and wrist. DXA-based 3D modeling showed significantly greater increases in hip cortical volumetric BMD with Abaloparatide versus teriparatide. This may explain differences reported in aBMD by DXA. In ACTIVE, Abaloparatide (ABL) increased bone mineral density (BMD) shown by dual-energy X-ray absorptiometry (DXA) while reducing fracture incidence in postmenopausal osteoporotic women. Changes in DXA BMD with ABL, 80 μg, were significantly greater than with open-label teriparatide (TPTD), 20 μg, at cortical sites including total hip, femoral neck, and 1/3 distal radius. The purpose of this study was to better understand the relative effects of ABL and TPTD on cortical and cancellous compartments in the proximal femur. Hip DXA images from a subset of randomly selected patients in the ACTIVE trial (n = 250/arm) were retrospectively analyzed using three-dimensional modeling methods (3D-SHAPER software) to evaluate changes from baseline at months 6 and 18. Similar significant increases in trabecular volumetric BMD (vBMD, + 9%) and cortical thickness (+ 1.5%) were observed with ABL and TPTD by 3D-DXA at 18 months. In contrast, only ABL significantly increased cortical vBMD versus baseline (+ 1.3%), and changes in both cortical vBMD and cortical surface BMD were significantly greater with ABL versus TPTD. In the TPTD group, changes in cortical vBMD were inversely correlated with changes in serum CTX (carboxy-terminal telopeptide of type I collagen) and PINP (procollagen type I N-terminal propeptide), suggesting that higher bone turnover may have attenuated cortical gains. These results suggest previously reported differences in areal BMD increases between ABL and TPTD may be due to differential effects on cortical vBMD. Further studies are warranted to investigate how these differences affect therapeutic impact on hip strength in postmenopausal women with osteoporosis.
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Differential effects of Abaloparatide and teriparatide on hip cortical volumetric BMD by DXA-based 3D modeling
Osteoporosis International, 2021Co-Authors: Renaud Winzenrieth, Y Wang, M S Ominsky, Ludovic Humbert, R J WeissAbstract:In postmenopausal osteoporotic women in ACTIVE, Abaloparatide reduced fracture risk and increased areal bone mineral density (BMD) more than teriparatide at the hip and wrist. DXA-based 3D modeling showed significantly greater increases in hip cortical volumetric BMD with Abaloparatide versus teriparatide. This may explain differences reported in aBMD by DXA. Introduction In ACTIVE, Abaloparatide (ABL) increased bone mineral density (BMD) shown by dual-energy X-ray absorptiometry (DXA) while reducing fracture incidence in postmenopausal osteoporotic women. Changes in DXA BMD with ABL, 80 μg, were significantly greater than with open-label teriparatide (TPTD), 20 μg, at cortical sites including total hip, femoral neck, and 1/3 distal radius. The purpose of this study was to better understand the relative effects of ABL and TPTD on cortical and cancellous compartments in the proximal femur. Methods Hip DXA images from a subset of randomly selected patients in the ACTIVE trial ( n = 250/arm) were retrospectively analyzed using three-dimensional modeling methods (3D-SHAPER software) to evaluate changes from baseline at months 6 and 18. Results Similar significant increases in trabecular volumetric BMD (vBMD, + 9%) and cortical thickness (+ 1.5%) were observed with ABL and TPTD by 3D-DXA at 18 months. In contrast, only ABL significantly increased cortical vBMD versus baseline (+ 1.3%), and changes in both cortical vBMD and cortical surface BMD were significantly greater with ABL versus TPTD. In the TPTD group, changes in cortical vBMD were inversely correlated with changes in serum CTX (carboxy-terminal telopeptide of type I collagen) and PINP (procollagen type I N-terminal propeptide), suggesting that higher bone turnover may have attenuated cortical gains. Conclusion These results suggest previously reported differences in areal BMD increases between ABL and TPTD may be due to differential effects on cortical vBMD. Further studies are warranted to investigate how these differences affect therapeutic impact on hip strength in postmenopausal women with osteoporosis.
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Forearm bone mineral density and fracture incidence in postmenopausal women with osteoporosis: results from the ACTIVExtend phase 3 trial
Osteoporosis International, 2021Co-Authors: Nelson B Watts, G. Hattersley, Y Wang, Robin K Dore, S. Baim, B. Mitlak, T.d. Rozental, M.s. LeboffAbstract:Abaloparatide increased ultradistal radius bone mineral density (BMD) in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. Over the subsequent 24 months in ACTIVExtend, ultradistal radius BMD gains were maintained with alendronate. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. Introduction Abaloparatide (ABL) increased femoral neck, total hip, and lumbar spine bone mineral density (BMD) in postmenopausal women with osteoporosis and decreased the risk of vertebral and nonvertebral fractures in ACTIVE. Effects on fracture risk and BMD were maintained subsequently with alendronate (ALN) in ACTIVExtend. In a prespecified subanalysis of ACTIVE, ABL also increased BMD at the ultradistal radius. Our objective was to determine the efficacy of ABL followed by ALN vs placebo (PBO) followed by ALN on forearm BMD and fracture risk over 43 months in ACTIVExtend. Methods Ultradistal and 1/3 radius BMD (ACTIVE baseline to month 43) were measured (ABL/ALN, n = 213; PBO/ALN, n = 233). Wrist fracture rates were estimated for the ACTIVExtend intent-to-treat population (ABL/ALN, n = 558; PBO/ALN, n = 581) by Kaplan-Meier (KM) method. Results At cumulative month 25, mean increase from ACTIVE baseline in ultradistal radius BMD was 1.1% (standard error, 0.49%) with ABL/ALN vs − 0.8% (0.43%) with PBO/ALN ( P
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forearm bone mineral density and fracture incidence in postmenopausal women with osteoporosis results from the activextend phase 3 trial
Osteoporosis International, 2021Co-Authors: Nelson B Watts, Gary Hattersley, Bruce H Mitlak, Y Wang, Robin K Dore, S. Baim, T.d. Rozental, M.s. LeboffAbstract:Abaloparatide increased ultradistal radius bone mineral density (BMD) in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. Over the subsequent 24 months in ACTIVExtend, ultradistal radius BMD gains were maintained with alendronate. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. Abaloparatide (ABL) increased femoral neck, total hip, and lumbar spine bone mineral density (BMD) in postmenopausal women with osteoporosis and decreased the risk of vertebral and nonvertebral fractures in ACTIVE. Effects on fracture risk and BMD were maintained subsequently with alendronate (ALN) in ACTIVExtend. In a prespecified subanalysis of ACTIVE, ABL also increased BMD at the ultradistal radius. Our objective was to determine the efficacy of ABL followed by ALN vs placebo (PBO) followed by ALN on forearm BMD and fracture risk over 43 months in ACTIVExtend. Ultradistal and 1/3 radius BMD (ACTIVE baseline to month 43) were measured (ABL/ALN, n = 213; PBO/ALN, n = 233). Wrist fracture rates were estimated for the ACTIVExtend intent-to-treat population (ABL/ALN, n = 558; PBO/ALN, n = 581) by Kaplan-Meier (KM) method. At cumulative month 25, mean increase from ACTIVE baseline in ultradistal radius BMD was 1.1% (standard error, 0.49%) with ABL/ALN vs − 0.8% (0.43%) with PBO/ALN (P < 0.01). BMD increases with ABL were maintained with ALN through month 43 in ACTIVExtend. BMD decreases at the 1/3 radius in ACTIVE (similar with ABL and PBO) were maintained through 24 months of ALN treatment in ACTIVExtend. Wrist fractures over 43 months occurred in 15 women with ABL/ALN (KM estimate, 2.8%) and 20 with PBO/ALN (KM estimate, 3.6%) (HR = 0.77, 95% CI 0.39, 1.50; P = not significant). Ultradistal radius BMD gains following treatment with ABL in ACTIVE were maintained over 24 months of ALN treatment in ACTIVExtend. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. ClinicalTrials.gov : NCT01657162 submitted July 31, 2012
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Characterizing patients initiating Abaloparatide, teriparatide, or denosumab in a real-world setting: a US linked claims and EMR database analysis
Osteoporosis International, 2020Co-Authors: E.a. Imel, Y Wang, R J Weiss, K. Starzyk, R. Gliklich, S.a. WilliamsAbstract:We characterized patients initiating Abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) in a real-world clinical setting from a large medical and pharmacy claims database. Differences were noted in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use for patients initiating ABL and TPTD compared with those receiving DMAB. Introduction To characterize patients initiating Abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) treatment in a real-world clinical setting. Methods Patients aged ≥ 18 years initiating ABL, TPTD, or DMAB between May 1, 2017, and September 24, 2018 (without receiving the same drug in the previous 12 months), were identified using the OM1 Data Cloud, which contains medical and pharmacy claims from approximately 200 million US patients. The index date was the date of initial prescription or dispensing for ABL, TPTD, or DMAB during the study period. Results During the study period, 2666 patients initiated ABL, 9210 TPTD, and 116,718 DMAB. Mean age (standard deviation) was 69.2 (10.6) years for the ABL cohort, 68.6 (11.3) for TPTD, and 72.1 (10.2) for DMAB ( P
