69 results on '"Gary, Hattersley"'
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2. Abaloparatide in Postmenopausal Women With Osteoporosis and Type 2 Diabetes: A Post Hoc Analysis of the ACTIVE Study
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Ruban Dhaliwal, Didier Hans, Gary Hattersley, Bruce Mitlak, Lorraine A Fitzpatrick, Yamei Wang, Ann V Schwartz, Paul D Miller, and Robert G Josse
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ABALOPARATIDE ,ANABOLICS ,BONE MINERAL DENSITY ,CLINICAL TRIALS ,DXA ,FRACTURE PREVENTION ,Orthopedic surgery ,RD701-811 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
ABSTRACT 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
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- 2020
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3. Data from Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor–Positive Breast Cancer Models with a Distinct Mechanism of Action
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Jamal C. Saeh, Gary Hattersley, Jeffrey L. Brown, Chris P. Miller, Hitisha K. Patel, Dannie Wang, Suqin He, and Ziyang Yu
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Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in in vivo and in vitro models of AR/ER+ breast cancer.Experimental Design: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models.Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib.Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1. It inhibits the growth of multiple AR/ER+ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER+ breast cancer patients. Clin Cancer Res; 23(24); 7608–20. ©2017 AACR.
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- 2023
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4. Supplementary Table from Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models
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Fiona Garner, Gary Hattersley, Dinesh M. Purandare, Jeffrey L. Brown, Hai Jiang, Nianjun Tao, Heike Arlt, Hitisha K. Patel, and Teeru Bihani
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Supplementary Table
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- 2023
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5. Supplementary Figures from Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models
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Fiona Garner, Gary Hattersley, Dinesh M. Purandare, Jeffrey L. Brown, Hai Jiang, Nianjun Tao, Heike Arlt, Hitisha K. Patel, and Teeru Bihani
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Supplementary Figures
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- 2023
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6. Supplementary Tables from Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor–Positive Breast Cancer Models with a Distinct Mechanism of Action
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Jamal C. Saeh, Gary Hattersley, Jeffrey L. Brown, Chris P. Miller, Hitisha K. Patel, Dannie Wang, Suqin He, and Ziyang Yu
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Supplementary Table S1. List of targets in the spectrum screen Supplementary Table S2. Characteristics of the breast cancer PDX models Supplementary Table S3. List of genes upregulated by more than 2-fold in RAD140-treated HBCx-22 xenografts
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- 2023
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7. Data from Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models
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Fiona Garner, Gary Hattersley, Dinesh M. Purandare, Jeffrey L. Brown, Hai Jiang, Nianjun Tao, Heike Arlt, Hitisha K. Patel, and Teeru Bihani
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Purpose: Estrogen receptor–positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer.Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models.Results: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations.Conclusions: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER+ disease. Clin Cancer Res; 23(16); 4793–804. ©2017 AACR.
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- 2023
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8. Forearm bone mineral density and fracture incidence in postmenopausal women with osteoporosis: results from the ACTIVExtend phase 3 trial
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Yamei Wang, Sanford Baim, Nelson B. Watts, Robin K. Dore, Tamara D. Rozental, Gary Hattersley, Meryl S. LeBoff, and Bruce H. Mitlak
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musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Population ,Urology ,030209 endocrinology & metabolism ,Radius bone ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Forearm ,Bone Density ,Bone mineral density ,Humans ,Medicine ,Wrist fracture ,education ,Osteoporosis, Postmenopausal ,Aged ,Femoral neck ,Bone mineral ,education.field_of_study ,Alendronate ,Bone Density Conservation Agents ,business.industry ,Incidence ,Middle Aged ,medicine.disease ,Postmenopause ,medicine.anatomical_structure ,Orthopedic surgery ,Original Article ,Female ,030101 anatomy & morphology ,business ,Osteoporotic Fractures - Abstract
Summary 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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- 2020
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9. Correction to: Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis
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Paul D. Miller, Nelson B. Watts, Gregory C. Williams, Felicia Cosman, Yamei Wang, Lorraine A. Fitzpatrick, and Gary Hattersley
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0301 basic medicine ,medicine.medical_specialty ,Abaloparatide ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,MEDLINE ,Dentistry ,030209 endocrinology & metabolism ,Kaplan-Meier Estimate ,03 medical and health sciences ,Absorptiometry, Photon ,0302 clinical medicine ,Double-Blind Method ,Bone Density ,Internal medicine ,medicine ,Humans ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Osteoporosis, Postmenopausal ,Aged ,Aged, 80 and over ,Bone Density Conservation Agents ,business.industry ,Parathyroid Hormone-Related Protein ,Correction ,Middle Aged ,Wrist Injuries ,medicine.disease ,Rheumatology ,Radius ,Mineral density ,Orthopedic surgery ,Forearm bone ,Female ,030101 anatomy & morphology ,WRIST FRACTURE ,Radius Fractures ,business ,Osteoporotic Fractures - Abstract
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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- 2020
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10. Effect of Abaloparatide vs Alendronate on Fracture Risk Reduction in Postmenopausal Women With Osteoporosis
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Gary Hattersley, Ming-yi Hu, Richard S. Bockman, Benjamin Z. Leder, and Bruce H. Mitlak
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Relative risk reduction ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Clinical Biochemistry ,Osteoporosis ,Urology ,030209 endocrinology & metabolism ,Context (language use) ,Placebo ,Biochemistry ,Placebos ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Endocrinology ,Bone Density ,Risk Factors ,Statistical significance ,Internal medicine ,Post-hoc analysis ,medicine ,Humans ,030212 general & internal medicine ,Poisson regression ,Osteoporosis, Postmenopausal ,Aged ,Lumbar Vertebrae ,Alendronate ,Bone Density Conservation Agents ,Femur Neck ,business.industry ,Biochemistry (medical) ,Parathyroid Hormone-Related Protein ,Middle Aged ,medicine.disease ,Radiography ,Treatment Outcome ,symbols ,Spinal Fractures ,Drug Therapy, Combination ,Female ,Erratum ,business ,Osteoporotic Fractures ,AcademicSubjects/MED00250 - Abstract
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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- 2019
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11. Fracture and Bone Mineral Density Response by Baseline Risk in Patients Treated With Abaloparatide Followed by Alendronate: Results From the Phase 3 ACTIVExtend Trial
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Ming Yi Hu, Nancy E Lane, Carol Zapalowski, Andrea Singer, Gary Hattersley, Benjamin Z. Leder, and Robin K. Dore
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Baseline risk ,030209 endocrinology & metabolism ,POSTMENOPAUSAL OSTEOPOROSIS ,Placebo ,Medical and Health Sciences ,03 medical and health sciences ,Engineering ,0302 clinical medicine ,Bone Density ,Risk Factors ,Internal medicine ,medicine ,Humans ,Orthopedics and Sports Medicine ,In patient ,Aged ,Femoral neck ,Bone mineral ,Alendronate ,BASELINE RISK SUBGROUPS ,Proportional hazards model ,business.industry ,Parathyroid Hormone-Related Protein ,Original Articles ,Biological Sciences ,Anatomy & Morphology ,FRACTURE PREVENTION ,030104 developmental biology ,medicine.anatomical_structure ,Relative risk ,ABALOPARATIDE ,Original Article ,business ,Risk Reduction Behavior ,Osteoporotic Fractures ,BONE MINERAL DENSITY - Abstract
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 (
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- 2019
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12. Abaloparatide increases bone mineral density and bone strength in ovariectomized rabbits with glucocorticoid-induced osteopenia
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Daniel J. Brooks, Mary L. Bouxsein, Gary Hattersley, Heidi Chandler, and Beate Lanske
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Trabecular architecture ,musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Ovariectomy ,Cortical bone ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,030209 endocrinology & metabolism ,Methylprednisolone ,03 medical and health sciences ,Absorptiometry, Photon ,0302 clinical medicine ,Bone Density ,Internal medicine ,medicine ,Animals ,Corticosteroid ,Femur ,Glucocorticoids ,Bone mineral ,Lumbar Vertebrae ,Bone Density Conservation Agents ,business.industry ,Parathyroid Hormone-Related Protein ,X-Ray Microtomography ,medicine.disease ,Biomechanical Phenomena ,Osteopenia ,Bone Diseases, Metabolic ,Endocrinology ,medicine.anatomical_structure ,Bone biomechanics ,Ovariectomized rat ,Female ,Original Article ,Rabbits ,030101 anatomy & morphology ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Summary Glucorticoid (GC) therapy is the commonest cause of secondary osteoporosis. Ovariectomized rabbits receiving the GC methylprednisolone for 6 weeks exhibited relatively lower vertebral and femoral bone mass. Treatment with the PTH receptor agonist abaloparatide for 12 weeks during ongoing methylprednisolone administration increased cortical and trabecular bone mass and femur bending strength. Introduction Abaloparatide, an osteoanabolic PTHrP analog, increases bone mineral density (BMD) and reduces fracture risk in women with postmenopausal osteoporosis. This study assessed abaloparatide effects on BMD and bone strength in ovariectomized (OVX) rabbits with glucocorticoid (GC)-induced osteopenia. Methods Thirty-two rabbits underwent OVX and 8 underwent sham surgery. One day later, 24 OVX rabbits began daily s.c. GC injections (methylprednisolone, 1 mg/kg/day) for 6 weeks, while 8 OVX and 8 sham controls received no GC. GC-challenged rabbits (8/group) then received GC (0.5 mg/kg/day) along with daily s.c. vehicle (GC-OVX), abaloparatide 5 μg/kg/day (ABL5), or 25 μg/kg/day (ABL25) for 12 weeks, and the no-GC OVX and sham controls received daily vehicle. Results GC-OVX rabbits showed significant deficits in vertebral and proximal femur areal BMD, lower cortical area, thickness and volumetric BMD of the femur diaphysis, and reduced trabecular bone volume and volumetric BMD in the vertebra and distal femur versus sham controls. These deficits were significantly reversed in the ABL25 group, which also showed enhanced trabecular micro-architecture versus GC-OVX controls. Destructive bending tests showed significantly lower femur diaphysis ultimate load and bending rigidity of the femoral diaphysis in the GC-OVX group versus sham controls, whereas these parameters were similar in the ABL25 group vs sham controls. Conclusions Abaloparatide 25 μg/kg/day mitigated the adverse effects of GC administration on cortical and trabecular bone and improved femoral strength in OVX rabbits. These results suggest potential promise for abaloparatide as an investigational therapy for glucocorticoid-induced osteoporosis.
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- 2019
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13. Abaloparatide, a PTH receptor agonist with homology to PTHrP, enhances callus bridging and biomechanical properties in rats with femoral fracture
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Allen Pierce, Heidi Chandler, Michael S. Ominsky, Jeffery Brown, Beate Lanske, Gary Hattersley, and Paul J. Kostenuik
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Male ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Abaloparatide ,0206 medical engineering ,Drug Evaluation, Preclinical ,02 engineering and technology ,Bone healing ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Orthopedics and Sports Medicine ,Bony Callus ,Endochondral ossification ,Receptor, Parathyroid Hormone, Type 1 ,Fracture Healing ,030203 arthritis & rheumatology ,Bone mineral ,business.industry ,Cartilage ,Parathyroid Hormone-Related Protein ,X-Ray Microtomography ,Femoral fracture ,medicine.disease ,020601 biomedical engineering ,medicine.anatomical_structure ,Endocrinology ,Callus ,business ,Femoral Fractures - Abstract
Fractures typically heal via endochondral and intramembranous bone formation, which together form a callus that achieves union and biomechanical recovery. PTHrP, a PTH receptor agonist, plays an important physiological role in fracture healing as an endogenous stimulator of endochondral and intramembranous bone formation. Abaloparatide, a novel systemically-administered osteoanabolic PTH receptor agonist that reduces fracture risk in women with postmenopausal osteoporosis, has 76% homology to PTHrP, suggesting it may have potential to improve fracture healing. To test this hypothesis, ninety-six 12-week-old male rats underwent unilateral internally-stabilized closed mid-diaphyseal femoral fractures and were treated starting the next day with daily s.c. saline (Vehicle) or abaloparatide at 5 or 20 µg/kg/d for 4 or 6 weeks (16 rats/group/time point). Histomorphometry and histology analyses indicated that fracture calluses from the abaloparatide groups exhibited significantly greater total area, higher fluorescence scores indicating more newly-formed bone, and higher fracture bridging scores versus Vehicle controls. Callus bridging score best correlated with callus cartilage score (r = 0.64) and fluorescence score (r = 0.67) at week 4, and callus area correlated with cartilage score (r = 0.60) and fluorescence score (r = 0.89) at Week 6. By micro-CT, calluses from one or both abaloparatide groups had greater bone volume, bone volume fraction, bone mineral content, bone mineral density, and cross-sectional area at both time points versus Vehicle controls. Destructive bending tests indicated greater callus maximum load and stiffness in one or both abaloparatide groups at both time points versus Vehicle controls. These results provide preliminary preclinical evidence for improved fracture healing with systemically-administered abaloparatide. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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- 2019
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14. Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis
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Gary Hattersley, Paul D. Miller, Lorraine A. Fitzpatrick, Nelson B. Watts, Felicia Cosman, Yamei Wang, and Gregory C. Williams
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Urology ,030209 endocrinology & metabolism ,Wrist ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Forearm ,Teriparatide ,medicine ,Bone mineral density ,Wrist fracture ,business.industry ,medicine.disease ,Confidence interval ,medicine.anatomical_structure ,Cortical bone ,Original Article ,030101 anatomy & morphology ,business ,medicine.drug - Abstract
Purpose 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. Methods 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). Results 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
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- 2019
15. Abaloparatide, a novel osteoanabolic PTHrP analog, increases cortical and trabecular bone mass and architecture in orchiectomized rats by increasing bone formation without increasing bone resorption
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Jeffrey L. Brown, Aurore Varela, Bruce H. Mitlak, Marilyne Boyer, Paul J. Kostenuik, Allen Pierce, Martin Guillot, Beate Lanske, Heidi Chandler, Gary Hattersley, Roland Baron, and Michael S. Ominsky
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Male ,musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,030209 endocrinology & metabolism ,Bone resorption ,Rats, Sprague-Dawley ,03 medical and health sciences ,Absorptiometry, Photon ,0302 clinical medicine ,Bone Density ,Osteogenesis ,Internal medicine ,Cortical Bone ,medicine ,Animals ,Femur ,Tibia ,Bone Resorption ,Quantitative computed tomography ,medicine.diagnostic_test ,business.industry ,Parathyroid Hormone-Related Protein ,Sham surgery ,Organ Size ,X-Ray Microtomography ,musculoskeletal system ,medicine.disease ,Osteopenia ,030104 developmental biology ,Endocrinology ,Cancellous Bone ,Bone Remodeling ,business ,Orchiectomy ,Biomarkers - Abstract
Male osteoporosis can occur with advanced age and with hypogonadism, with increased bone resorption and/or inadequate bone formation contributing to reduced bone mass and increased fracture risk. Abaloparatide is a selective PTH receptor agonist that increases bone formation and bone mass in postmenopausal women with osteoporosis and in estrogen-deficient animals. The current study evaluated the effects of abaloparatide in orchiectomized (ORX) rats, a model of male osteoporosis. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery; 8 weeks later the ORX groups exhibited relative osteopenia vs sham controls, based on dual X-ray absorptiometry (DXA) and/or peripheral quantitative computed tomography (pQCT) assessments at the total body, lumbar spine, femur, and tibia. ORX rats (n = 10/group) were then injected daily (s.c.) for 8 weeks with vehicle or abaloparatide at 5 (ABL5) or 25 μg/kg/d (ABL25). Sham controls (n = 10) received s.c. vehicle. DXA and pQCT showed that one or both abaloparatide groups gained more areal and volumetric BMD at all sites analyzed compared with vehicle controls, leading to substantial or complete reversal of ORX-induced BMD deficits. pQCT also indicated greater gains in tibial cortical thickness in both abaloparatide groups versus vehicle controls. Tibial bone histomorphometry showed greater trabecular bone formation and bone volume and improved micro-architecture with abaloparatide, with no increase in osteoclasts. Abaloparatide also led to significant improvements in the balance of biochemical bone formation markers versus bone resorption markers, which correlated with BMD changes. These findings suggest that abaloparatide may have therapeutic benefits in men with osteoporosis.
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- 2019
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16. Abaloparatide in Postmenopausal Women With Osteoporosis and Type 2 Diabetes: A Post Hoc Analysis of the ACTIVE Study
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Bruce H. Mitlak, Paul D. Miller, Ann V. Schwartz, Ruban Dhaliwal, Yamei Wang, Didier Hans, Gary Hattersley, Robert G. Josse, and Lorraine A. Fitzpatrick
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medicine.medical_specialty ,ANABOLICS ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Population ,Diseases of the musculoskeletal system ,Placebo ,OSTEOPOROSIS ,ABALOPARATIDE ,BONE MINERAL DENSITY ,CLINICAL TRIALS ,DXA ,FRACTURE PREVENTION ,TRABECULAR BONE SCORE ,TYPE 2 DIABETES MELLITUS ,Trabecular bone score ,Internal medicine ,Post-hoc analysis ,medicine ,Teriparatide ,Orthopedics and Sports Medicine ,education ,Femoral neck ,Orthopedic surgery ,education.field_of_study ,business.industry ,medicine.disease ,medicine.anatomical_structure ,RC925-935 ,Original Article ,business ,RD701-811 ,medicine.drug - Abstract
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
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- 2020
17. Abaloparatide is an Effective Treatment Option for Postmenopausal Osteoporosis: Review of the Number Needed to Treat Compared with Teriparatide
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Ming-yi Hu, Jean-Yves Reginster, Gregory C. Williams, Gary Hattersley, E. Michael Lewiecki, and Lorraine A. Fitzpatrick
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0301 basic medicine ,Relative risk reduction ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Urology ,030209 endocrinology & metabolism ,Placebo ,ACTIVE trial ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Postmenopausal osteoporosis ,Teriparatide ,medicine ,Humans ,Orthopedics and Sports Medicine ,Osteoporosis, Postmenopausal ,Original Research ,Aged ,Aged, 80 and over ,Number needed to treat ,Bone Density Conservation Agents ,business.industry ,Absolute risk reduction ,Parathyroid Hormone-Related Protein ,Middle Aged ,medicine.disease ,030104 developmental biology ,Research Design ,Orthopedic surgery ,Fracture risk reduction ,Female ,business ,Osteoporotic Fractures ,medicine.drug - Abstract
Abaloparatide (ABL) is a 34-amino acid peptide designed to be a selective activator of the parathyroid hormone receptor type 1 signaling pathway. In the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), subcutaneous ABL reduced the risk of new vertebral, nonvertebral, clinical, and major osteoporotic fracture compared with placebo and of major osteoporotic fracture compared with teriparatide. To further evaluate the effectiveness of ABL, we calculated the number needed to treat (NNT) to prevent one fracture using ACTIVE data. To estimate the potential effectiveness of ABL in populations at higher fracture risk than in ACTIVE, we calculated NNT for vertebral fracture using reference populations from historical placebo-controlled trials, assuming an 86% relative risk reduction in vertebral fracture with ABL treatment as observed in ACTIVE. NNT was calculated as the reciprocal of the absolute risk reduction in ACTIVE. The projected NNT for ABL in other populations was calculated based on incidence rate (IR) for vertebral fractures in the placebo arms of the FREEDOM (placebo IR 7.2%), FIT-1 (placebo IR 15.0%), and FIT-2 (placebo IR 3.8%) trials. NNT for ABL in ACTIVE was 28 for vertebral, 55 for nonvertebral, 37 for clinical, and 34 for major osteoporotic fracture. NNT for these fracture types for teriparatide in ACTIVE were 30, 92, 59, and 75, respectively. Using placebo IRs from FREEDOM, FIT-1, and FIT-2, projected NNTs for vertebral fracture with ABL were 17, 8, and 31. These data are useful for further evaluating ABL for the treatment of osteoporosis in postmenopausal women.
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- 2018
18. Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption
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Solomon Haile, Susan Y. Smith, Robert E. Guldberg, Gary Hattersley, Michael S. Ominsky, Aurore Varela, Nancy Doyle, and Paul J. Kostenuik
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0301 basic medicine ,medicine.medical_specialty ,Bone quality ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Ovariectomy ,Osteoporosis ,030209 endocrinology & metabolism ,Bone strength ,Bone resorption ,Bone remodeling ,03 medical and health sciences ,0302 clinical medicine ,Absorptiometry, Photon ,Bone Density ,Osteogenesis ,Internal medicine ,medicine ,Animals ,Bone Resorption ,Femoral neck ,Receptor, Parathyroid Hormone, Type 1 ,PTH1R ,Lumbar Vertebrae ,Bone Density Conservation Agents ,business.industry ,Parathyroid Hormone-Related Protein ,X-Ray Microtomography ,medicine.disease ,Peptide Fragments ,Resorption ,Macaca fascicularis ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Ovariectomized rat ,Original Article ,Female ,Densitometry ,business ,Biomarkers ,Procollagen - Abstract
Summary Abaloparatide, a novel PTH1 receptor agonist, increased bone formation in osteopenic ovariectomized cynomolgus monkeys while increasing cortical and trabecular bone mass. Abaloparatide increased bone strength and maintained or enhanced bone mass-strength relationships, indicating preserved or improved bone quality. Introduction Abaloparatide is a selective PTH1R activator that is approved for the treatment of postmenopausal osteoporosis. The effects of 16 months of abaloparatide administration on bone formation, resorption, density, and strength were assessed in adult ovariectomized (OVX) cynomolgus monkeys (cynos). Methods Sixty-five 9–18-year-old female cynos underwent OVX surgery, and 15 similar cynos underwent sham surgery. After a 9-month period without treatments, OVX cynos were allocated to four groups that received 16 months of daily s.c. injections with either vehicle (n = 17) or abaloparatide (0.2, 1, or 5 μg/kg/day; n = 16/dose level), while Sham controls received s.c. vehicle (n = 15). Bone densitometry (DXA, pQCT, micro-CT), qualitative bone histology, serum calcium, bone turnover markers, bone histomorphometry, and bone strength were among the key measures assessed. Results At the end of the 9-month post-surgical bone depletion period, just prior to the treatment phase, the OVX groups exhibited increased bone turnover markers and decreased bone mass compared with sham controls. Abaloparatide administration to OVX cynos led to increased bone formation parameters, including serum P1NP and endocortical bone formation rate. Abaloparatide administration did not influence serum calcium levels, bone resorption markers, cortical porosity, or eroded surfaces. Abaloparatide increased bone mass at the whole body, lumbar spine, tibial diaphysis, femoral neck, and femoral trochanter. Abaloparatide administration was associated with greater lumbar vertebral strength, and had no adverse effects on bone mass-strength relationships for the vertebrae, femoral neck, femoral diaphysis, or humeral cortical beams. Conclusions Abaloparatide administration was associated with increases in bone formation, bone mass and bone strength, and with maintenance of bone quality in OVX cynos, without increases in serum calcium or bone resorption parameters. Electronic supplementary material The online version of this article (10.1007/s00198-017-4323-6) contains supplementary material, which is available to authorized users.
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- 2017
19. Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide
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Paul D. Miller, Gary Hattersley, Yamei Wang, Michael R. McClung, Gregory C. Williams, and Lorraine A. Fitzpatrick
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FRAX ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,030209 endocrinology & metabolism ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Randomized controlled trial ,law ,medicine ,Orthopedics and Sports Medicine ,030212 general & internal medicine ,Original Research ,Hip fracture ,Geography ,Incidence (epidemiology) ,Hazard ratio ,medicine.disease ,Fracture ,Relative risk ,Demography - Abstract
Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non-vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities.
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- 2017
20. Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models
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Jeffrey L. Brown, D Purandare, F Garner, Hitisha K. Patel, Gary Hattersley, Teeru Bihani, Hai Jiang, Nianjun Tao, and Heike Arlt
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0301 basic medicine ,Cancer Research ,Everolimus ,Combination therapy ,medicine.drug_class ,business.industry ,Estrogen receptor ,Cancer ,Palbociclib ,Pharmacology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,Oncology ,Estrogen ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,business ,Estrogen receptor alpha ,medicine.drug - Abstract
Purpose: Estrogen receptor–positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models. Results: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations. Conclusions: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER+ disease. Clin Cancer Res; 23(16); 4793–804. ©2017 AACR.
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- 2017
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21. One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats
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Paul J. Kostenuik, Robert E. Guldberg, Aurore Varela, Elisabeth Lesage, Susan Y. Smith, Luc Chouinard, and Gary Hattersley
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musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Histology ,Physiology ,Ovariectomy ,Abaloparatide ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,030209 endocrinology & metabolism ,Bone and Bones ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Femur ,Tibia ,Receptor, Parathyroid Hormone, Type 1 ,business.industry ,Parathyroid Hormone-Related Protein ,Sham surgery ,Organ Size ,medicine.disease ,Biomechanical Phenomena ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Ovariectomized rat ,Female ,Cortical bone ,Tomography, X-Ray Computed ,business ,Densitometry - Abstract
Abaloparatide is a novel 34 amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor 1 (PTHR1) signaling pathway. The effects of 12months of abaloparatide treatment on bone mass, bone strength and bone quality was assessed in osteopenic ovariectomized (OVX) rats. SD rats were subjected to OVX or sham surgery at 6months of age and left untreated for 3months to allow OVX-induced bone loss. Eighteen OVX rats were sacrificed after this bone depletion period, and the remaining OVX rats received daily s.c. injections of vehicle (n=18) or abaloparatide at 1, 5 or 25μg/kg/d (n=18/dose level) for 12months. Sham controls (n=18) received vehicle daily. Bone changes were assessed by DXA and pQCT after 0, 3, 6 or 12months of treatment, and destructive biomechanical testing was conducted at month 12 to assess bone strength and bone quality. Abaloparatide dose-dependently increased bone mass at the lumbar spine and at the proximal and diaphyseal regions of the tibia and femur. pQCT revealed that increased cortical bone volume at the tibia was a result of periosteal expansion and endocortical bone apposition. Abaloparatide dose-dependently increased structural strength of L4-L5 vertebral bodies, the femur diaphysis, and the femur neck. Increments in peak load for lumbar spine and the femur diaphysis of abaloparatide-treated rats persisted even after adjusting for treatment-related increments in BMC, and estimated material properties were maintained or increased at the femur diaphysis with abaloparatide. The abaloparatide groups also exhibited significant and positive correlations between bone mass and bone strength at these sites. These data indicate that gains in cortical and trabecular bone mass with abaloparatide are accompanied by and correlated with improvements in bone strength, resulting in maintenance or improvement in bone quality. Thus, this study demonstrated that long-term daily administration of abaloparatide to osteopenic OVX rats led to dose-dependent improvements in bone mass, geometry and strength.
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- 2017
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22. Eighteen Months of Treatment With Subcutaneous Abaloparatide Followed by 6 Months of Treatment With Alendronate in Postmenopausal Women With Osteoporosis
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John P. Bilezikian, Ming-yi Hu, Lorraine A. Fitzpatrick, Claus Christiansen, Bente Juel Riis, Felicia Cosman, Gregory C. Williams, Paul D. Miller, Gary Hattersley, Dennis M. Black, and Ivo Valter
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Medicine(all) ,0301 basic medicine ,Relative risk reduction ,medicine.medical_specialty ,Intention-to-treat analysis ,Bone density ,business.industry ,Abaloparatide ,Osteoporosis ,030209 endocrinology & metabolism ,General Medicine ,medicine.disease ,Interim analysis ,Placebo ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Teriparatide ,Medicine ,business ,medicine.drug - Abstract
Objective To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis). Patients and Methods ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients. Results Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P Conclusion Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis. Trial Registration clinicaltrials.gov Identifier: NCT01657162.
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- 2017
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23. Abaloparatide in patients with mild or moderate renal impairment: results from the ACTIVE phase 3 trial
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Gary Hattersley, Ming-yi Hu, Bruce H. Mitlak, C. Dabrowski, Socrates E. Papapoulos, John P. Bilezikian, Lorraine A. Fitzpatrick, and Paul D. Miller
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medicine.medical_specialty ,Post hoc ,Abaloparatide ,Osteoporosis ,Urology ,030204 cardiovascular system & hematology ,Kidney ,Degree (temperature) ,03 medical and health sciences ,Fractures, Bone ,0302 clinical medicine ,bone regeneration ,Double-Blind Method ,Active phase ,Teriparatide ,medicine ,Humans ,In patient ,030212 general & internal medicine ,abaloparatide ,Renal Insufficiency ,Bone regeneration ,Osteoporosis, Postmenopausal ,Aged ,postmenopausal ,Bone Density Conservation Agents ,business.industry ,Parathyroid Hormone-Related Protein ,General Medicine ,Middle Aged ,medicine.disease ,Treatment Outcome ,Female ,Drug Monitoring ,business ,Tomography, X-Ray Computed ,Glomerular Filtration Rate - Abstract
Objective: 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, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80 mu g, placebo, or open-label teriparatide 20 mu g daily. Patients with serum creatinine >2.0 mg/dL or 1.5-2.0 mg/dL with an estimated glomerular filtration rate (eGFR) = 90 mL/min, 1276 had 60 to
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- 2019
24. One Year of Abaloparatide, a Selective Activator of the PTH1 Receptor, Increased Bone Formation and Bone Mass in Osteopenic Ovariectomized Rats Without Increasing Bone Resorption
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Susan Y. Smith, Luc Chouinard, Aurore Varela, Gary Hattersley, and Elisabeth Lesage
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0301 basic medicine ,Bone mineral ,medicine.medical_specialty ,Bone density ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,030209 endocrinology & metabolism ,medicine.disease ,Bone resorption ,Resorption ,Bone remodeling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,Ovariectomized rat ,Medicine ,Orthopedics and Sports Medicine ,Cortical bone ,business - Abstract
Abaloparatide is a novel 34-amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor (PTH1R) signaling pathway with 41% homology to PTH(1-34) and 76% homology to PTHrP(1-34). A 12-month treatment study was conducted in osteopenic ovariectomized (OVX) rats to characterize the mechanisms by which abaloparatide increases bone mass. Sprague-Dawley (SD) rats were subjected to OVX or sham surgery at age 6 months and left untreated for 3 months to allow OVX-induced bone loss. Ten OVX rats were euthanized after this bone depletion period, and the remaining OVX rats received daily subcutaneous injections of vehicle (n = 18) or abaloparatide at 1, 5, or 25 μg/kg/d (n = 18/dose level) for 12 months. Sham controls (n = 18) received vehicle daily. Bone densitometry and biochemical markers of bone formation and resorption were assessed longitudinally, and L3 vertebra and tibia were collected at necropsy for histomorphometry. Abaloparatide increased biochemical bone formation markers without increasing bone resorption markers or causing hypercalcemia. Abaloparatide increased histomorphometric indices of bone formation on trabecular, endocortical, and periosteal surfaces without increasing osteoclasts or eroded surfaces. Abaloparatide induced substantial increases in trabecular bone volume and density and improvements in trabecular microarchitecture. Abaloparatide stimulated periosteal expansion and endocortical bone apposition at the tibial diaphysis, leading to marked increases in cortical bone volume and density. Whole-body bone mineral density (BMD) remained stable in OVX-Vehicle controls while increasing 25% after 12 months of abaloparatide (25 μg/kg). Histomorphometry and biomarker data suggest that gains in cortical and trabecular bone mass were attributable to selective anabolic effects of abaloparatide, without evidence for stimulated bone resorption. © 2016 American Society for Bone and Mineral Research.
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- 2016
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25. Effects of Abaloparatide-SC on Fractures and Bone Mineral Density in Subgroups of Postmenopausal Women With Osteoporosis and Varying Baseline Risk Factors
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Lorraine A. Fitzpatrick, Ming-yi Hu, Gregory C. Williams, Gary Hattersley, Dennis M. Black, and Felicia Cosman
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0301 basic medicine ,Bone mineral ,medicine.medical_specialty ,Postmenopausal women ,Bone density ,business.industry ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Baseline risk ,030209 endocrinology & metabolism ,Odds ratio ,medicine.disease ,Placebo ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,medicine ,Orthopedics and Sports Medicine ,business - Abstract
Abaloparatide-SC is a novel 34-amino acid peptide created to be a potent and selective activator of the parathyroid hormone receptor type 1 (PTHR1) signaling pathway. In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) Phase 3 trial (NCT01343004), abaloparatide reduced new morphometric vertebral fractures by 86% compared with placebo (p -2.5 and ≤-3.0 versus >-3.0), history of nonvertebral fracture (yes versus no), prevalent vertebral fracture (yes versus no), and age (
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- 2016
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26. Six Weeks of Daily Abaloparatide Treatment Increased Vertebral and Femoral Bone Mineral Density, Microarchitecture and Strength in Ovariectomized Osteopenic Rats
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Kyla Gallacher, Julie Downall, Gary Hattersley, Carol A. Nelson, Hila Bahar, and Maysoun Shomali
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0301 basic medicine ,musculoskeletal diseases ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,PTHrP ,Ovariectomy ,Osteoporosis ,PTHR1 ,030209 endocrinology & metabolism ,Bone strength ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Absorptiometry, Photon ,Bone Density ,Internal medicine ,medicine ,Animals ,Orthopedics and Sports Medicine ,Femur ,Original Research ,Bone mineral ,Lumbar Vertebrae ,Bone Density Conservation Agents ,business.industry ,Parathyroid Hormone-Related Protein ,X-Ray Microtomography ,Anabolic treatment ,medicine.disease ,Vertebra ,Rats ,Bone Diseases, Metabolic ,030104 developmental biology ,medicine.anatomical_structure ,Orthopedic surgery ,Ovariectomized rat ,Female ,business ,hormones, hormone substitutes, and hormone antagonists ,PTH - Abstract
Abaloparatide is a novel, potent and selective activator of parathyroid hormone receptor 1 (PTHR1) under clinical development for the treatment of osteoporosis. We assessed the effect of 6 weeks of abaloparatide on bone mass, microarchitecture, quality and strength in ovariectomized (OVX) rats. After 8 weeks of post-surgical bone depletion (baseline), OVX rats (n = 20–21/group) received daily subcutaneous vehicle (OVX-Veh) or abaloparatide at 5 or 20 µg/kg. Sham-operated control rats (n = 24) received vehicle. Areal bone mineral density (aBMD) of the lumbar spine (L4), total femur and femur diaphysis was measured at baseline and after 6 weeks of treatment. Femur and vertebral bone architecture and mechanical properties were assessed at the end of the treatment phase. At baseline, OVX-Veh rats exhibited significantly lower aBMD relative to Sham controls. Treatment of OVX rats with abaloparatide at 5 or 20 µg/kg/day increased aBMD dose-dependently in the lumbar spine, total femur and femur diaphysis to levels exceeding OVX-Veh or Sham controls. The abaloparatide 5 and 20 µg/kg groups had improved trabecular microarchitecture relative to OVX vehicle, with trabecular BV/TV exceeding OVX-Veh control values by 57 and 78 % (respectively) at the lumbar spine, and by 145 and 270 % at the distal femur. Femur diaphyseal cortical volume and thickness were significantly greater in the abaloparatide 20 µg/kg group relative to OVX vehicle or Sham controls. Bone strength parameters of the femur diaphysis, femur neck and L4 vertebra were significantly improved in the OVX-ABL groups relative to OVX-Veh controls. Bone mass–strength relationships and estimated intrinsic strength properties suggested maintained or improved bone quality with abaloparatide. These data demonstrate skeletal restoration via abaloparatide treatment of osteopenic OVX rats, in association with improved trabecular microarchitecture, cortical geometry and bone strength at sites that have clinical relevance in patients with osteoporosis.
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- 2016
27. Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling
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Braden Corbin, Hila Bahar, Thomas J. Gardella, Thomas Dean, and Gary Hattersley
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Models, Molecular ,0301 basic medicine ,medicine.medical_specialty ,MAP Kinase Signaling System ,Protein Conformation ,Parathyroid hormone ,030209 endocrinology & metabolism ,Ligands ,Second Messenger Systems ,Bone resorption ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,GTP-Binding Proteins ,Genes, Reporter ,Internal medicine ,Cyclic AMP ,medicine ,Humans ,Receptor ,Binding selectivity ,Receptor, Parathyroid Hormone, Type 1 ,Original Research ,Binding Sites ,ABL ,Bone Density Conservation Agents ,Parathyroid hormone receptor ,Chemistry ,Cell Membrane ,HEK 293 cells ,Parathyroid Hormone-Related Protein ,Peptide Fragments ,Recombinant Proteins ,Kinetics ,HEK293 Cells ,030104 developmental biology ,Guanosine 5'-O-(3-Thiotriphosphate) ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists - Abstract
The PTH receptor type 1 (PTHR1) mediates the actions of two endogenous polypeptide ligands, PTH and PTHrP, and thereby plays key roles in bone biology. Based on its capacity to stimulate bone formation, the peptide fragment PTH (1–34) is currently in use as therapy for osteoporosis. Abaloparatide (ABL) is a novel synthetic analog of human PTHrP (1–34) that holds promise as a new osteoporosis therapy, as studies in animals suggest that it can stimulate bone formation with less of the accompanying bone resorption and hypercalcemic effects that can occur with PTH (1–34). Recent studies in vitro suggest that certain PTH or PTHrP ligand analogs can distinguish between two high-affinity PTHR1 conformations, R0 and RG, and that efficient binding to R0 results in prolonged signaling responses in cells and prolonged calcemic responses in animals, whereas selective binding to RG results in more transient responses. As intermittent PTH ligand action is known to favor the bone-formation response, whereas continuous ligand action favors the net bone-resorption/calcemic response, we hypothesized that ABL binds more selectively to the RG vs the R0 PTHR1 conformation than does PTH (1–34), and thus induces more transient signaling responses in cells. We show that ABL indeed binds with greater selectivity to the RG conformation than does PTH (1–34), and as a result of this RG bias, ABL mediates more transient cAMP responses in PTHR1-expressing cells. The findings provide a plausible mechanism (ie, transient signaling via RG-selective binding) that can help account for the favorable anabolic effects that ABL has on bone.
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- 2016
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28. ERRATUM for 'Effect of Abaloparatide vs Alendronate on Fracture Risk Reduction in Postmenopausal Women With Osteoporosis'
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Bruce H. Mitlak, Benjamin Z. Leder, Richard S. Bockman, Gary Hattersley, and Ming-yi Hu
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Fracture risk ,medicine.medical_specialty ,Postmenopausal women ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Abaloparatide ,Biochemistry (medical) ,Clinical Biochemistry ,Osteoporosis ,Urology ,medicine.disease ,Biochemistry ,Endocrinology ,Internal medicine ,medicine ,business ,Reduction (orthopedic surgery) - Published
- 2020
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29. Abaloparatide improves cortical geometry and trabecular microarchitecture and increases vertebral and femoral neck strength in a rat model of male osteoporosis
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Tatiana Besschetnova, Michael S. Ominsky, Dorothy Hu, Bruce H. Mitlak, Gary Hattersley, Beate Lanske, Kenichi Nagano, Daniel J. Brooks, Roland Baron, Mary L. Bouxsein, and Jordan L. Nustad
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0301 basic medicine ,Male ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Urology ,030209 endocrinology & metabolism ,Bone resorption ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Osteoclast ,Androgen deficiency ,medicine ,Cortical Bone ,Animals ,Femoral neck ,business.industry ,Femur Neck ,Parathyroid Hormone-Related Protein ,Osteoblast ,Organ Size ,X-Ray Microtomography ,medicine.disease ,Spine ,Vertebra ,Biomechanical Phenomena ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Cancellous Bone ,business - Abstract
Androgen deficiency is a leading cause of male osteoporosis, with bone loss driven by an inadequate level of bone formation relative to the extent of bone resorption. Abaloparatide, an osteoanabolic PTH receptor agonist used to treat women with postmenopausal osteoporosis at high risk for fracture, increases bone formation and bone strength in estrogen-deficient animals without increasing bone resorption. This study examined the effects of abaloparatide on bone formation, bone mass, and bone strength in androgen-deficient orchiectomized (ORX) rats, a male osteoporosis model. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery. Eight weeks later, sham-operated rats received vehicle (saline; n = 10) while ORX rats (n = 10/group) received vehicle (Veh) or abaloparatide at 5 or 25 μg/kg (ABL5 or ABL25) by daily s.c. injection for 8 weeks, followed by sacrifice. Dynamic bone histomorphometry indicated that the tibial diaphysis of one or both abaloparatide groups had higher periosteal mineralizing surface, intracortical bone formation rate (BFR), endocortical BFR, and cortical thickness vs Veh controls. Vertebral trabecular BFR was also higher in both abaloparatide groups vs Veh, and the ABL25 group had higher trabecular osteoblast surface without increased osteoclast surface. By micro-CT, the vertebra and distal femur of both abaloparatide-groups had improved trabecular bone volume and micro-architecture, and the femur diaphysis of the ABL25 group had greater cortical thickness with no increase in porosity vs Veh. Biomechanical testing indicated that both abaloparatide-groups had stronger vertebrae and femoral necks vs Veh controls. These findings provide preclinical support for evaluating abaloparatide as an investigational treatment for male osteoporosis.
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- 2018
30. ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis
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John P. Bilezikian, Paul D. Miller, Robin K. Dore, Ming-yi Hu, Henry G. Bone, Bruce H. Mitlak, Gary Hattersley, Felicia Cosman, Kenneth G. Saag, S. Papapoulos, Gregory C. Williams, Lorraine A. Fitzpatrick, and René Rizzoli
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medicine.medical_specialty ,Parathyroid, Bone, and Mineral Metabolism ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Clinical Biochemistry ,Osteoporosis ,MEDLINE ,030209 endocrinology & metabolism ,Postmenopausal osteoporosis ,Placebo ,Biochemistry ,Drug Substitution ,Drug Administration Schedule ,law.invention ,Maintenance Chemotherapy ,Placebos ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Randomized controlled trial ,law ,Bone Density ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Osteoporosis, Postmenopausal ,Clinical Research Articles ,Maintenance chemotherapy ,Aged ,Aged, 80 and over ,ddc:616 ,Alendronate ,Bone Density Conservation Agents ,business.industry ,Femur Neck ,Biochemistry (medical) ,Parathyroid Hormone-Related Protein ,Middle Aged ,medicine.disease ,Spinal Fractures ,Female ,business ,Osteoporotic Fractures - Abstract
Purpose In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results Five hundred fifty-eight women from ACTIVE’s ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan–Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Conclusions Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures., In ACTIVExtend, reductions in fracture risk and increases in BMD achieved with 18 months of abaloparatide for postmenopausal osteoporosis were sustained through 24 months of subsequent alendronate.
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- 2018
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31. Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: Results from the ACTIVE phase 3 trial
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Edith M. C. Lau, Paul D. Miller, Lorraine A. Fitzpatrick, Ming-yi Hu, Gregory C. Williams, Luis A. Russo, Bente Juel Riis, C. Christiansen, Gary Hattersley, and Alan G. Harris
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0301 basic medicine ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Urology ,Phases of clinical research ,030209 endocrinology & metabolism ,Postmenopausal osteoporosis ,Placebo ,Bone and Bones ,Placebos ,03 medical and health sciences ,0302 clinical medicine ,Bone Density ,Teriparatide ,medicine ,Humans ,Femoral neck ,Aged ,Bone mineral ,business.industry ,Parathyroid Hormone-Related Protein ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Female ,business ,medicine.drug - Abstract
Abaloparatide is a 34-amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE.Proportions of patients experiencing BMD gains from baseline of0%,3%, and6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites.At months 6, 12, and 18, there were significantly more3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the0% and6% responder thresholds.In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.
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- 2018
32. Effects of abaloparatide on bone mineral density and risk of fracture in postmenopausal women aged 80 years or older with osteoporosis
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Lorraine A. Fitzpatrick, Paul D. Miller, Nicholas C. Harvey, Michael R. McClung, Felicia Cosman, Yamei Wang, and Gary Hattersley
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medicine.medical_specialty ,fracture risk ,Abaloparatide ,Fracture (mineralogy) ,Osteoporosis ,postmenopausal women ,030209 endocrinology & metabolism ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,Bone Density ,Risk Factors ,law ,Internal medicine ,older ,medicine ,Humans ,abaloparatide ,030212 general & internal medicine ,Risk factor ,Pelvic Bones ,Osteoporosis, Postmenopausal ,Aged, 80 and over ,Bone mineral ,Lumbar Vertebrae ,Bone Density Conservation Agents ,Femur Neck ,business.industry ,Incidence ,Incidence (epidemiology) ,Parathyroid Hormone-Related Protein ,Obstetrics and Gynecology ,medicine.disease ,Postmenopause ,Clinical trial ,Treatment Outcome ,Spinal Fractures ,Female ,bone mineral density ,business ,Osteoporotic Fractures - Abstract
Objective: Advanced age is an important risk factor for fracture. The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) trial showed that subcutaneous abaloparatide increased bone mineral density (BMD) and reduced the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. This study describes the effects of abaloparatide in the subgroup of women aged 80 or more years in ACTIVE. Methods: Post hoc analyses of BMD and fracture incidence in this subgroup of women who received abaloparatide or placebo in the 18-month, phase 3, double-blind, randomized controlled ACTIVE trial. Results: The mean ages of the women ≥80 years were 81.9 and 81.7 years in the placebo (n = 43) and abaloparatide (n = 51) groups, respectively. The increases in BMD from baseline to 18 months with abaloparatide treatment were 3.9% at the total hip (P
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- 2018
33. Abaloparatide-SC improves trabecular microarchitecture as assessed by trabecular bone score (TBS): a 24-week randomized clinical trial
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Didier Hans, Enisa Shevroja, Jose R. Zanchetta, Lorraine A. Fitzpatrick, Gary Hattersley, Benjamin Z. Leder, J. P. Bilezikian, K. Banks, and Alan G. Harris
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0301 basic medicine ,medicine.medical_specialty ,Bone density ,Injections, Subcutaneous ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Anabolics ,Bone microarchitecture ,Clinical trials ,Osteoporosis ,Urology ,030209 endocrinology & metabolism ,Lumbar vertebrae ,03 medical and health sciences ,Absorptiometry, Photon ,0302 clinical medicine ,Trabecular bone score ,Double-Blind Method ,Bone Density ,Teriparatide ,medicine ,Humans ,Osteoporosis, Postmenopausal ,Aged ,Aged, 80 and over ,Bone mineral ,Lumbar Vertebrae ,Bone Density Conservation Agents ,Dose-Response Relationship, Drug ,business.industry ,Parathyroid Hormone-Related Protein ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Cancellous Bone ,Original Article ,Female ,business ,Cancellous bone ,Osteoporotic Fractures ,medicine.drug - Abstract
Summary In a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to one of three different doses of abaloparatide-SC, subcutaneous teriparatide, or placebo for 24 weeks, abaloparatide-SC resulted in improvements in skeletal microarchitecture as measured by the trabecular bone score. Introduction Subcutaneous abaloparatide (abaloparatide-SC) increases total hip and lumbar spine bone mineral density and reduces vertebral and non-vertebral fractures. In this study, we analyzed the extent to which abaloparatide-SC improves skeletal microarchitecture, assessed indirectly by trabecular bone score (TBS). Methods This is a post hoc analysis of a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to abaloparatide-SC (20, 40, or 80 μg), subcutaneous teriparatide (20 μg), or placebo for 24 weeks. TBS was measured from lumbar spine dual X-ray absorptiometry (DXA) images in 138 women for whom the DXA device was TBS software compatible. Assessments were made at baseline, 12 and 24 weeks. Between-group differences were assessed by generalized estimating equations adjusted for relevant baseline characteristics, and a pre-determined least significant change analysis was performed. Results After 24 weeks, TBS increased significantly by 2.27, 3.14, and 4.21% versus baseline in participants on 20, 40, and 80 μg abaloparatide-SC daily, respectively, and by 2.21% in those on teriparatide (p
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- 2018
34. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models
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Maysoun Shomali, Dotty Paquin, F Garner, C. Richard Lyttle, and Gary Hattersley
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Cancer Research ,estrogen receptor inhibition ,Estrogen receptor ,Administration, Oral ,blood–brain barrier ,Rats, Sprague-Dawley ,Bone Density ,Medicine ,Preclinical Reports ,Pharmacology (medical) ,ortho-Aminobenzoates ,Aromatase ,biology ,Brain Neoplasms ,anticancer activity ,tissue selectivity ,Oncology ,Selective estrogen receptor modulator ,MCF-7 Cells ,Heterografts ,Female ,medicine.drug ,medicine.medical_specialty ,medicine.drug_class ,Ovariectomy ,Mice, Nude ,Antineoplastic Agents ,Breast Neoplasms ,Binding, Competitive ,Breast cancer ,breast cancer ,Internal medicine ,Animals ,selective estrogen receptor degraders ,Cell Proliferation ,Pharmacology ,Fulvestrant ,business.industry ,Phenylurea Compounds ,Uterus ,Estrogen Receptor alpha ,Cancer ,medicine.disease ,Endocrinology ,selective estrogen receptor modulators ,Estrogen ,biology.protein ,Cancer research ,Osteoporosis ,business ,Estrogen receptor alpha ,Neoplasm Transplantation - Abstract
Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.
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- 2015
35. Effects of Abaloparatide, a Human Parathyroid Hormone-Related Peptide Analog, on Bone Mineral Density in Postmenopausal Women with Osteoporosis
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Jose R. Zanchetta, Louis St. L. O’Dea, C. Richard Lyttle, Kathleen Banks, Benjamin Z. Leder, Gary Hattersley, Prasana Kumar, and Kathleen McKay
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musculoskeletal diseases ,medicine.medical_specialty ,Bone density ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Clinical Biochemistry ,Osteoporosis ,Biochemistry ,Bone remodeling ,Endocrinology ,Double-Blind Method ,Bone Density ,Teriparatide ,Internal medicine ,medicine ,Humans ,Osteoporosis, Postmenopausal ,Aged ,Femoral neck ,Aged, 80 and over ,Bone mineral ,Lumbar Vertebrae ,Peptide analog ,Bone Density Conservation Agents ,Femur Neck ,business.industry ,Biochemistry (medical) ,Parathyroid Hormone-Related Protein ,Middle Aged ,medicine.disease ,Radiography ,Treatment Outcome ,medicine.anatomical_structure ,Female ,business ,medicine.drug - Abstract
Abaloparatide is a novel synthetic peptide analog of parathyroid hormone-related protein (PTHrP) that is currently being developed as a potential anabolic agent in the treatment of postmenopausal osteoporosis.This study sought to assess the effects of abaloparatide on bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck in postmenopausal women with osteoporosis.Multi-center, multi-national, double-blind placebo controlled trial in which postmenopausal women were randomly assigned to receive 24 weeks of treatment with daily sc injections of placebo, abaloparatide, 20, 40, or 80 μg, or teriparatide, 20 μg. A 24-week extension was also performed in a subset of subjects.Postmenopausal women with osteoporosis (n = 222).BMD by dual-x-ray absorptiometry and biochemical markers of bone turnover.At 24 weeks, lumbar spine BMD increased by 2.9, 5.2, and 6.7% in the abaloparatide, 20-, 40-, and 80-μg groups, respectively, and 5.5% in the teriparatide group. The increases in the 40- and 80-μg abaloparatide groups and the teriparatide group were significantly greater than placebo (1.6%). Femoral neck BMD increased by 2.7, 2.2, and 3.1% in abaloparatide, 20-, 40-, and 80-μg groups, respectively, and 1.1% in the teriparatide group. The increase in femoral neck BMD with abaloparatide, 80 μg was significantly greater than placebo (0.8%). Total hip BMD increased by 1.4, 2.0, and 2.6% in the abaloparatide, 20-, 40-, and 80-μg groups, respectively. The total hip increases in the 40- and 80-μg abaloparatide groups were greater than both placebo (0.4%) and teriparatide (0.5%).Compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion. Moreover, the abaloparatide-induced BMD increases at the total hip are greater than with the marketed dose of teriparatide. These results support the further investigation of abaloparatide as an anabolic therapy in postmenopausal osteoporosis.
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- 2015
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36. Abstract P3-05-07: RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model
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F Garner, John A. Katzenellenbogen, Gary Hattersley, Jeffrey L. Brown, and CR Lyttle
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Cancer Research ,Fulvestrant ,business.industry ,Wild type ,Estrogen receptor ,Cancer ,Pharmacology ,medicine.disease ,Metastatic breast cancer ,Breast cancer ,Oncology ,medicine ,Cancer research ,business ,Estrogen receptor alpha ,Tamoxifen ,medicine.drug - Abstract
Despite advances in the treatment of metastatic breast cancer, many women eventually relapse with more aggressive forms of endocrine-resistant disease. Mutations in the ESR1 gene encoding the estrogen receptor (ER) have recently emerged as a potential mechanism for the development of clinical resistance to conventional anti-estrogen therapies, such as fulvestrant. To overcome some of the pharmacokinetic limitations and intramuscular administration challenges associated with fulvestrant endocrine therapy and to combat the development of resistance, there is a significant need for the development of more durable and more effective ER-targeted therapies. Here, we begin to describe and characterize the preclinical efficacy of RAD1901, a novel, orally bioavailable small-molecule SERD, with significant therapeutic potential for treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 demonstrated profound tumor growth inhibition in MCF-7 xenograft models when compared to fulvestrant and tamoxifen. Importantly, RAD1901 also demonstrated marked single agent efficacy in a primary patient-derived xenograft (PDx) model harboring the ESR1 Y537S mutation indicating the utility of this SERD against clinically relevant ER mutants. Further biochemical binding studies and co-crystallization experiments of RAD1901 bound to the ER further confirms the ability of RAD1901 to bind to both mutant and wild type forms of the ER. RAD1901 is currently undergoing clinical testing in postmenopausal women with ER-positive advanced breast cancer. Citation Format: Garner F, Brown J, Katzenellenbogen J, Lyttle CR, Hattersley G. RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-07.
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- 2016
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37. Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor-Positive Breast Cancer Models with a Distinct Mechanism of Action
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Suqin He, Jeffrey L. Brown, Gary Hattersley, Ziyang Yu, Hitisha K. Patel, Dannie Wang, Jamal Carlos Saeh, and Chris Miller
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0301 basic medicine ,Cancer Research ,Estrogen receptor ,Breast Neoplasms ,Palbociclib ,Pharmacology ,03 medical and health sciences ,Prostate cancer ,Mice ,0302 clinical medicine ,Breast cancer ,Nitriles ,medicine ,Animals ,Humans ,Cell Proliferation ,Oxadiazoles ,business.industry ,Estrogen Receptor alpha ,Cancer ,Estrogens ,medicine.disease ,Xenograft Model Antitumor Assays ,Androgen receptor ,030104 developmental biology ,Oncology ,Selective androgen receptor modulator ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Androgens ,MCF-7 Cells ,Female ,business ,Estrogen receptor alpha - Abstract
Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in in vivo and in vitro models of AR/ER+ breast cancer. Experimental Design: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models. Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib. Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1. It inhibits the growth of multiple AR/ER+ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER+ breast cancer patients. Clin Cancer Res; 23(24); 7608–20. ©2017 AACR.
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- 2017
38. Selective Androgen Receptor Modulator RAD140 Is Neuroprotective in Cultured Neurons and Kainate-Lesioned Male Rats
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Christian J. Pike, Gary Hattersley, Rebekah S. Vest, Anusha Jayaraman, Chris Miller, Amy Christensen, and V. Alexandra Moser
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Male ,Risk ,Agonist ,Kainic acid ,medicine.medical_specialty ,Cell Survival ,medicine.drug_class ,Apoptosis ,Kainate receptor ,Biology ,Pharmacology ,Hippocampus ,Neuroprotection ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Prostate cancer ,Hormone Antagonists ,Endocrinology ,Internal medicine ,Nitriles ,medicine ,Animals ,Cells, Cultured ,Testosterone ,Neurons ,Oxadiazoles ,Kainic Acid ,Neurodegenerative Diseases ,Neuroendocrinology ,medicine.disease ,Rats ,Androgen receptor ,Neuroprotective Agents ,chemistry ,Selective androgen receptor modulator ,Acetanilides ,Female ,Signal Transduction - Abstract
The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed “selective androgen receptor modulators” (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.
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- 2014
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39. Persistent Fracture Reduction with Abaloparatide-SC (TYMLOS™) Followed by 24 Months of Alendronate
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Kenneth G. Saag, Paul D. Miller, Robin K. Dore, Felicia Cosman, J. P. Bilezikian, B Mitlak, Lorraine A. Fitzpatrick, and Gary Hattersley
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Relative risk reduction ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Endocrinology, Diabetes and Metabolism ,Incidence (epidemiology) ,Abaloparatide ,Osteoporosis ,Population ,medicine.disease ,Placebo ,Internal medicine ,medicine ,Teriparatide ,Radiology, Nuclear Medicine and imaging ,Orthopedics and Sports Medicine ,Osteonecrosis of the jaw ,business ,education ,medicine.drug - Abstract
Introduction In the ACTIVE phase III trial, 2463 postmenopausal women with osteoporosis were randomized 1:1:1 to abaloparatide (ABL; n=824), blinded placebo (PBO; n=821), or open-label teriparatide (n=818). During ACTIVE, ABL increased BMD and reduced vertebral, nonvertebral, clinical, and major osteoporotic fractures compared to PBO. Women who completed ABL or PBO treatment in ACTIVE were eligible to enroll in an extension study (ACTIVExtend) to receive up to 24 months of open-label alendronate (ALN). Objectives To provide additional safety information and to evaluate vertebral and nonvertebral fracture endpoints. Methods The ACTIVExtend study enrolled 558 women from the original ABL group and 581 from the PBO group of the ACTIVE study (92% of women who completed ABL or PBO treatment in ACTIVE). Pre-specified endpoints, including vertebral, nonvertebral, clinical, and major osteoporotic fractures, were assessed over the 43-month period from ACTIVE baseline to the end of ACTIVExtend (18 months of ABL or PBO treatment, 1 month for reconsent, and 24 months of ALN treatment). Nonvertebral fracture endpoints were assessed using the Kaplan-Meier (KM) method, proportional hazard model, and logrank test for patients enrolled in ACTIVExtend and for the full ITT population randomized to ABL or PBO treatment in ACTIVE. Results During the 43-month period, 5.6% (n=32) of evaluable women sustained a new morphometric vertebral fracture in the PBO followed by ALN (PBO/ALN) group compared to 0.9% (n=5) in the ABL/ALN group, an 84% relative risk reduction (p The Table shows the KM rates of nonvertebral fracture endpoints over 43 months from ACTIVE baseline through the end of ACTIVExtend for both the ACTIVExtend cohorts as well as the full ACTIVE ITT population. The incidence of adverse events (AEs) including severe and serious AEs during ALN treatment period was similar for both study groups. The most common AEs were arthralgia, URI, and back pain. No cases of atypical femoral fracture or osteonecrosis of the jaw were reported. Conclusions In the ACTIVExtend study, administration of ABL for 18 months followed by ALN for 24 months resulted in sustained vertebral and nonvertebral fracture reduction compared to PBO followed by ALN. In the full randomized ACTIVE ITT population, over 43 months, in the ABL + ABL/ALN groups, there was a significant reduction in the incidence of vertebral and nonvertebral fractures as well as hip fractures compared to the PBO + PBO/ALN groups.
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- 2018
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40. Abstract #530 Effect of Abaloparatide Versus Alendronate on Fracture Risk Reduction in Postmenopausal Women with Osteoporosis
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Greg Williams, Naim M. Maalouf, Benjamin Z. Leder, Bruce H. Mitlak, Gary Hattersley, and Ming-yi Hu
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Fracture risk ,medicine.medical_specialty ,Postmenopausal women ,business.industry ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,medicine.medical_treatment ,Osteoporosis ,General Medicine ,medicine.disease ,Endocrinology ,Internal medicine ,medicine ,business ,Reduction (orthopedic surgery) - Published
- 2018
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41. Abstract #531 Effect of Abaloparatide on Bone Mineral Density and Fracture Incidence in Postmenopausal Women with Osteoporosis and Type 2 Diabetes Mellitus
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Lorraine A. Fitzpatrick, Paul Miller, Bruce H. Mitlak, Ann V. Schwartz, Didier Hans, Yamei Wang, Ruban Dhaliwal, Gary Hattersley, and Robert G. Josse
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Bone mineral ,medicine.medical_specialty ,Postmenopausal women ,business.industry ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Incidence (epidemiology) ,Fracture (mineralogy) ,Osteoporosis ,Type 2 Diabetes Mellitus ,General Medicine ,medicine.disease ,Endocrinology ,Internal medicine ,medicine ,business - Published
- 2018
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42. Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34)
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Gerald G. Long, Bassem Attalla, Sabile Trimm, Jacquelin Jolette, Susan Y. Smith, Nacera Mellal, Aurore Varela, Gary Hattersley, and Michael S. Ominsky
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0301 basic medicine ,Agonist ,medicine.medical_specialty ,Bone density ,medicine.drug_class ,Abaloparatide ,Osteoporosis ,Parathyroid hormone ,030209 endocrinology & metabolism ,Bone Neoplasms ,Toxicology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Osteosarcoma ,Parathyroid hormone-related protein ,Bone Density Conservation Agents ,business.industry ,Incidence ,Parathyroid Hormone-Related Protein ,General Medicine ,medicine.disease ,Rats, Inbred F344 ,Rats ,030104 developmental biology ,Endocrinology ,Parathyroid Hormone ,Female ,business ,Hormone - Abstract
Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.
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- 2016
43. Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER
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Teeru, Bihani, Hitisha K, Patel, Heike, Arlt, Nianjun, Tao, Hai, Jiang, Jeffrey L, Brown, Dinesh M, Purandare, Gary, Hattersley, and Fiona, Garner
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Selective Estrogen Receptor Modulators ,Mice, Inbred BALB C ,Tetrahydronaphthalenes ,Pyridines ,Mice, Nude ,Antineoplastic Agents ,Breast Neoplasms ,Xenograft Model Antitumor Assays ,Piperazines ,Tumor Burden ,Receptors, Estrogen ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,MCF-7 Cells ,Animals ,Humans ,Female ,Everolimus - Published
- 2016
44. Clinical investigation of RAD1901, a novel estrogen receptor ligand, for the treatment of postmenopausal vasomotor symptoms: a phase 2 randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial
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Alan G. Harris, Gary Hattersley, Ginger D. Constantine, and James A. Simon
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Adult ,Selective Estrogen Receptor Modulators ,medicine.medical_specialty ,Tetrahydronaphthalenes ,General Mathematics ,Placebo ,Ligands ,Gastroenterology ,Severity of Illness Index ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,Severity of illness ,medicine ,Humans ,Adverse effect ,Gynecology ,030219 obstetrics & reproductive medicine ,Vasomotor ,Dose-Response Relationship, Drug ,business.industry ,Applied Mathematics ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Menopause ,Clinical trial ,Postmenopause ,Vasomotor System ,Treatment Outcome ,Selective estrogen receptor modulator ,030220 oncology & carcinogenesis ,Hot Flashes ,Female ,business - Abstract
Objective The aim of the study was to assess the efficacy and safety of RAD1901, an oral estrogen receptor ligand, for the treatment of moderate-to-severe vasomotor symptoms of menopause. Methods This was a randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial. Postmenopausal women with a minimum of 7 moderate-to-severe, diary-reported hot flashes per day, or 50 per week, were randomized to one of five blinded dose groups (0 [placebo], 10, 25, 50, or 100 mg RAD1901 daily for 28 d). Efficacy endpoints included frequency and severity of hot flashes over 4 weeks of treatment. Results One hundred participants were randomized across the five treatment regimens. The frequency of moderate-to-severe hot flashes decreased in all groups over the treatment period (mean percent change from baseline at 4 wk, -54.1%, -77.2%, -51.8%, -53.8%, and -67.0% for placebo, 10, 25, 50, and 100 mg groups). The response in the 10 mg group was significantly different from placebo at 4 weeks (P = 0.024). No other dose group was significantly different from placebo. There were no statistically significant differences in severity of hot flashes between placebo and any dose group. Treatment was well tolerated; most treatment-emergent adverse events were mild to moderate in severity. Conclusions Daily treatment with 10 mg RAD1901 over 4 weeks resulted in a statistically significant reduction in the frequency of moderate-to-severe hot flashes compared with placebo, with an acceptable safety profile. Further clinical trials are warranted to investigate RAD1901's utility as a potential treatment for vasomotor symptoms.
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- 2016
45. Effects of Abaloparatide-SC on Fractures and Bone Mineral Density in Subgroups of Postmenopausal Women With Osteoporosis and Varying Baseline Risk Factors
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Felicia, Cosman, Gary, Hattersley, Ming-Yi, Hu, Gregory C, Williams, Lorraine A, Fitzpatrick, and Dennis M, Black
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Aged, 80 and over ,Postmenopause ,Bone Density ,Risk Factors ,Odds Ratio ,Parathyroid Hormone-Related Protein ,Humans ,Osteoporosis ,Female ,Middle Aged ,Osteoporotic Fractures ,Aged - Abstract
Abaloparatide-SC is a novel 34-amino acid peptide created to be a potent and selective activator of the parathyroid hormone receptor type 1 (PTHR1) signaling pathway. In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) Phase 3 trial (NCT01343004), abaloparatide reduced new morphometric vertebral fractures by 86% compared with placebo (p 0.001) and nonvertebral fractures by 43% (p = 0.049) in postmenopausal women with osteoporosis. Abaloparatide-SC increased bone mineral density (BMD) 3.4% at the total hip, 2.9% at the femoral neck, and 9.2% at the lumbar spine at 18 months (all p 0.001 versus placebo). The analysis reported here was designed to evaluate whether fracture risk reductions and BMD accrual were consistent across different levels of baseline risk. Risk factor subgroups were predefined categorically for BMD T-score of the lumbar spine, total hip, and femoral neck (≤-2.5 versus-2.5 and ≤-3.0 versus-3.0), history of nonvertebral fracture (yes versus no), prevalent vertebral fracture (yes versus no), and age (65 versus 65 to75 versus ≥75 years) at baseline. Forest plots show that there were no clinically meaningful interactions between any of the baseline risk factors and the treatment effect of abaloparatide-SC on new morphometric vertebral fractures, nonvertebral fractures, or BMD increases. Abaloparatide provides protection against fractures consistently across a wide variety of ages and baseline risks, including those with and without prior fractures, and it has potential utility for a broad group of postmenopausal women with osteoporosis. © 2016 American Society for Bone and Mineral Research.
- Published
- 2016
46. Eighteen Months of Treatment With Subcutaneous Abaloparatide Followed by 6 Months of Treatment With Alendronate in Postmenopausal Women With Osteoporosis: Results of the ACTIVExtend Trial
- Author
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Felicia, Cosman, Paul D, Miller, Gregory C, Williams, Gary, Hattersley, Ming-Yi, Hu, Ivo, Valter, Lorraine A, Fitzpatrick, Bente Juel, Riis, Claus, Christiansen, John P, Bilezikian, and Dennis, Black
- Subjects
Aged, 80 and over ,Alendronate ,Bone Density Conservation Agents ,Injections, Subcutaneous ,Parathyroid Hormone-Related Protein ,Kaplan-Meier Estimate ,Middle Aged ,Bone Density ,Humans ,Spinal Fractures ,Female ,Osteoporosis, Postmenopausal ,Osteoporotic Fractures ,Aged ,Proportional Hazards Models - Abstract
To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis).ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients.Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P.001). Kaplan-Meier estimated rates of nonvertebral fractures were PBO/ALN, 5.6% vs ABL-SC/ALN, 2.7%; risk reduction, 52% (hazard ratio [HR], 0.48; 95% CI, 0.26-0.89; log-rank P=.02). There was also a 58% risk reduction of major osteoporotic fractures (HR, 0.42; 95% CI, 0.21-0.85; log-rank P=.01) and a 45% risk reduction of clinical fractures (HR, 0.55; 95% CI, 0.33-0.92; log-rank P=.02) in the ABL-SC/ALN group vs the PBO/ALN group. At 25 months, bone mineral density percentage change from ACTIVE baseline for ABL-SC/ALN vs PBO/ALN was as follows: lumbar spine, 12.8%; total hip, 5.5%; femoral neck, 4.5% vs 3.5%, 1.4%, 0.5%, respectively (group differences at all sites P.001).Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis.clinicaltrials.gov Identifier: NCT01657162.
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- 2016
47. Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140
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John A. Katzenellenbogen, Matthew S. Burge, C. Richard Lyttle, Kyla Gallacher, Jennifer L. Green, Gary Hattersley, Maysoun Shomali, Alexei Tchesnokov, Dottie Paquin, Louis St. L. O’Dea, Dennis R. Compton, Hillary Herendeen, Bishwabhusan Sahoo, Chris P. Miller, Sean Kerrigan, and Michael Nickels
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Nonsteroidal ,medicine.drug_class ,business.industry ,Anabolic androgen ,Organic Chemistry ,Pharmacology ,urologic and male genital diseases ,Androgen ,Biochemistry ,chemistry.chemical_compound ,Design synthesis ,chemistry ,Selective androgen receptor modulator ,Drug Discovery ,medicine ,business - Abstract
This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.
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- 2010
- Full Text
- View/download PDF
48. Effects of Abaloparatide-SC on Fractures and Bone Mineral Density in Subgroups of Postmenopausal Women with Osteoporosis and Varying Baseline Risk Factors
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Gary Hattersley, Gregory C. Williams, Dennis M. Black, Lorraine A. Fitzpatrick, Felicia Cosman, and Ming-yi Hu
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030203 arthritis & rheumatology ,Bone mineral ,030222 orthopedics ,medicine.medical_specialty ,Postmenopausal women ,business.industry ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Baseline risk ,medicine.disease ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Radiology, Nuclear Medicine and imaging ,Orthopedics and Sports Medicine ,Treatment effect ,business - Abstract
Abaloparatide-SC is a novel 34-amino acid peptide created to be a potent and selective activator of the parathyroid hormone receptor type 1 (PTHR1) signaling pathway. In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) Phase 3 trial (NCT01343004), abaloparatide reduced new morphometric vertebral fractures by 86% compared with placebo (p -2.5 and ≤-3.0 versus >-3.0), history of nonvertebral fracture (yes versus no), prevalent vertebral fracture (yes versus no), and age (
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- 2018
- Full Text
- View/download PDF
49. Correction to: Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide
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Lorraine A. Fitzpatrick, Gary Hattersley, Michael R. McClung, Gregory C. Williams, Paul D. Miller, and Yamei Wang
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abaloparatide ,Osteoporosis ,Internet portal ,Endocrinology ,medicine ,Humans ,Orthopedics and Sports Medicine ,Osteoporosis, Postmenopausal ,Aged ,Aged, 80 and over ,Postmenopausal women ,Bone Density Conservation Agents ,General surgery ,Incidence (epidemiology) ,Incidence ,Parathyroid Hormone-Related Protein ,Correction ,Middle Aged ,medicine.disease ,Postmenopause ,Treatment Outcome ,Spinal Fractures ,Female ,Osteoporotic Fractures - Abstract
Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non-vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities.
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- 2018
50. Effects of transforming growth factor β1 on the regulation of osteoclastic development and function
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Gary Hattersley and Timothy J. Chambers
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Calcitonin ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Cellular differentiation ,Osteoclasts ,Bone Marrow Cells ,Receptors, Cell Surface ,Biology ,Bone resorption ,Iodine Radioisotopes ,Mice ,Transforming Growth Factor beta ,Osteoclast ,Internal medicine ,Bone cell ,medicine ,Animals ,Orthopedics and Sports Medicine ,Bone Resorption ,Cells, Cultured ,Rats, Inbred Strains ,Transforming growth factor beta ,Receptors, Calcitonin ,Rats ,Resorption ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,Animals, Newborn ,Mice, Inbred CBA ,biology.protein ,Autoradiography ,Bone marrow ,Transforming growth factor - Abstract
Transforming growth factor (TGF) beta 1 is a multifunctional cytokine with powerful effects on osteoblastic cells. Its role in the regulation of osteoclast generation and function, however, is unclear. It has been reported both to stimulate and to inhibit resorption in organ culture and to inhibit multinuclear cell formation in bone marrow cultures. We tested the effects of TGF-beta 1 on bone resorption by osteoclasts isolated from neonatal rat long bones. We found potent stimulation of osteoclastic bone resorption, mediated by osteoblastic cells, with an EC50 of 10 pg/ml, considerably lower than that of well-documented osteotropic hormones. Stimulation was not mediated by Swiss mouse 3T3 cells, a nonosteoblastic cell line. TGF-beta 1 strongly inhibited the generation of calcitonin receptor (CTR)-positive cells in mouse bone marrow cultures, but as for isolated osteoclasts, bone resorption per CTR-positive cell was increased. The inhibition of CTR-positive cell formation was associated with suppression of maturation of other bone marrow derivatives and may be related more to the known ability of TGF-beta 1 to suppress the proliferation of primitive hematopoietic cells than to a specific role of TGF-beta 1 in osteoclast generation.
- Published
- 2009
- Full Text
- View/download PDF
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