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Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis

Primary Purpose

Osteopenia, Osteoporosis

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Denosumab
Sponsored by
Amgen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteopenia focused on measuring postmenopausal osteoporosis, low bone density, fractures, low bone mass

Eligibility Criteria

60 Years - 94 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Postmenopausal women who have attended the 20030216 (NCT00089791) study month 36 visit will be eligible to participate if they meet the inclusion and exclusion criteria given below.

Inclusion Criteria

  • Subjects must sign the informed consent before any study specific procedures are performed and agree to receive denosumab 60 mg subcutaneous injection every 6 months
  • Subjects must not have discontinued investigational product during the 20030216 study and must have attended the 20030216 study month 36 visit
  • Subjects must be re-consented prior to (or at) the 24 month visit for participation beyond month 24.

Exclusion Criteria

  • Permanently non-ambulatory subjects (use of an assistive device eg, cane, walker, etc. is permitted)
  • Missed 2 or more investigational product doses during the 20030216 study
  • Any disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures
  • Developed sensitivity to mammalian cell derived drug products during the 20030216 study
  • Unable to tolerate calcium supplementation during the last 6 months of participation in the 20030216 study (between the month 30 and month 36 20030216 study visits)
  • Currently receiving any investigational product other than denosumab or having received any investigational product during the 20030216 study
  • Current use of the following osteoporosis agents: bisphosphonates, calcitonin, fluoride, parathyroid hormone, selective estrogen receptor modulators, systemic oral or transdermal estrogen (except vaginal preparations and estrogen creams which are acceptable), strontium, or tibolone
  • For bone biopsy sub-study subjects only: known or suspected sensitivity or contraindication to tetracycline derivatives

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Denosumab

    Arm Description

    Participants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years.

    Outcomes

    Primary Outcome Measures

    Number of Participants With Adverse Events (AEs)
    A serious adverse event (SAE) is defined as an adverse event that: • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is other significant medical hazard. Treatment-related adverse events includes only events for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. The following were classified as adverse events of interest (events that are considered to be identified or potential risks of denosumab treatment): positively adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral fracture, hypocalcemia, adverse events potentially related to hypersensitivity, serious infection (including bacterial cellulitis), malignancy, cardiac disorders, vascular disorders, fracture healing complications, eczema, acute pancreatitis, and musculoskeletal pain.
    Number of Participants With Laboratory Toxicities of Grade ≥ 3
    Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity.
    Number of Participants With Antibodies to Denosumab

    Secondary Outcome Measures

    Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
    Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit
    1/3 radius bone mineral density was measured in a subset of participants by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit
    Lumbar spine bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit
    1/3 radius BMD was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Number of Participants With New Vertebral Fractures
    A new vertebral fracture, assessed by lateral spine X-ray using Genant semiquantitative scoring method, was identified as an ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4, excluding any fracture associated with high trauma severity or a pathologic fracture.
    Number of Participants With Non-Vertebral Fractures
    Non-vertebral fractures (osteoporotic) were defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging (MRI) confirming the fracture, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
    Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new sparticipants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Percent Change From Study 20030216 Baseline in CTX-1 by Visit
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Percent Change From Study 20030216 Baseline in P1NP by Visit
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
    Serum Denosumab Concentration
    Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 0.8 ng/mL. Values of 0 in the table below indicate data below the lower limit of quantification.
    Bone Histomorphometry: Cancellous Bone Volume
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by quantitative histomorphometry.
    Bone Histomorphometry: Trabecular Number
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular number is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Trabecular number is a measure of trabecular connectivity and decreases with bone loss.
    Bone Histomorphometry: Trabecular Separation
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular separation is the mean distance between trabeculae (measured by integrated computer graphics). Trabecular separation increases with trabecular bone loss.
    Bone Histomorphometry: Trabecular Thickness
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Mean trabecular thickness is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Trabecular thickness is reduced by aging and osteoporosis.
    Bone Histomorphometry: Cortical Width
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices.
    Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by tartrate-resistant acid phosphatase (TRAP) staining histomorphometry.
    Bone Histomorphometry: Surface Density
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume.
    Bone Histomorphometry: Osteoblast - Osteoid Interface
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100.
    Bone Histomorphometry: Osteoid Surface
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid.
    Bone Histomorphometry: Osteoid Thickness
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid thickness (width) is the mean thickness of osteoid seams on cancellous surfaces. Osteoid thickness is normally <12.5 µm. Increased osteoid thickness suggests abnormal mineralization (osteomalacia).
    Bone Histomorphometry: Wall Thickness
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Wall thickness is the average thickness of trabecular bone structural units (BSU) and is used to assess the overall balance between resorption and formation.
    Bone Histomorphometry: Eroded Surface/Bone Surface
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Eroded surface/bone surface is the percentage of bone surface occupied by eroded (resorption) cavities (Howships lacunae), with or without osteoclasts.
    Bone Histomorphometry: Osteoclast Number - Length Based
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per mm of bone.
    Bone Histomorphometry: Osteoclast Number - Surface Based
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per 100 mm of bone surface area.
    Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per mm of bone.
    Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per 100 mm of bone surface. Da
    Bone Histomorphometry: Single-label Surface
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. A single label is deposited if formation either started or ended during the interval between the uses of the two courses of tetracycline administration. Single-label surface is expressed as a percentage of total bone surface.
    Bone Histomorphometry: Double-label Surface
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The presence of double labels indicates that normal bone mineralization was actively occurring over the entire labeling interval. Double-label surface is expressed as a percentage of total bone surface.
    Bone Histomorphometry: Mineralizing Surface
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface.
    Bone Histomorphometry: Mineral Apposition Rate
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. MAR is calculated as the average distance between visible labels, divided by the labeling interval.
    Bone Histomorphometry: Adjusted Apposition Rate
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the average rate at which new bone mineral is being added on any actively forming surface. Adjusted MAR is calculated as: (average distance between visible labels / labeling interval) * (total mineralizing surface/total bone surface).
    Bone Histomorphometry: Bone Formation Rate - Surface Based
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - surface based is the calculated rate at which cancellous bone surface is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone surface).
    Bone Histomorphometry: Bone Formation Rate - Volume Based
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - volume based is the calculated rate at which cancellous bone volume is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone volume).
    Bone Histomorphometry: Formation Period
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Formation period (FP) is the mean time required to rebuild a new bone structural unit or osteon from the cement line back to the bone surface at a single location, and is given by wall width / adjusted apposition rate.
    Bone Histomorphometry: Activation Frequency
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The average time that it takes for a new remodeling cycle to begin on any point on a cancellous surface is called the activation frequency. Activation frequency is calculated as the bone formation rate / wall width.
    Bone Histomorphometry: Osteoid Volume
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid volume is the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).
    Bone Histomorphometry: Mineralization Lag Time
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Mineralization lag time is the average time interval between osteoid formation and its subsequent mineralization and is calculated by dividing the osteoid width by the apposition rate.
    Bone Histology at Month 24
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.
    Bone Histology at Month 84
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.

    Full Information

    First Posted
    August 30, 2007
    Last Updated
    November 4, 2022
    Sponsor
    Amgen
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00523341
    Brief Title
    Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis
    Official Title
    An Open Label, Single Arm, Extension Study to Evaluate the Long Term Safety and Sustained Efficacy of Denosumab (AMG162) in the Treatment of Postmenopausal Osteoporosis
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2022
    Overall Recruitment Status
    Completed
    Study Start Date
    August 7, 2007 (Actual)
    Primary Completion Date
    July 19, 2015 (Actual)
    Study Completion Date
    July 19, 2015 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Amgen

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The primary objective was to describe the safety and tolerability of up to 10 years or 7 years denosumab administration as measured by adverse event monitoring, immunogenicity and safety laboratory parameters in participants who previously received denosumab or placebo, respectively.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Osteopenia, Osteoporosis
    Keywords
    postmenopausal osteoporosis, low bone density, fractures, low bone mass

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    4550 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Denosumab
    Arm Type
    Experimental
    Arm Description
    Participants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years.
    Intervention Type
    Biological
    Intervention Name(s)
    Denosumab
    Other Intervention Name(s)
    AMG 162, Prolia
    Intervention Description
    Administered by subcutaneous injection once every 6 months.
    Primary Outcome Measure Information:
    Title
    Number of Participants With Adverse Events (AEs)
    Description
    A serious adverse event (SAE) is defined as an adverse event that: • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is other significant medical hazard. Treatment-related adverse events includes only events for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. The following were classified as adverse events of interest (events that are considered to be identified or potential risks of denosumab treatment): positively adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral fracture, hypocalcemia, adverse events potentially related to hypersensitivity, serious infection (including bacterial cellulitis), malignancy, cardiac disorders, vascular disorders, fracture healing complications, eczema, acute pancreatitis, and musculoskeletal pain.
    Time Frame
    84 months
    Title
    Number of Participants With Laboratory Toxicities of Grade ≥ 3
    Description
    Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity.
    Time Frame
    84 months
    Title
    Number of Participants With Antibodies to Denosumab
    Time Frame
    Every 12 months through Month 84
    Secondary Outcome Measure Information:
    Title
    Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
    Description
    Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Time Frame
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    Title
    Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
    Description
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Time Frame
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    Title
    Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
    Description
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Time Frame
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    Title
    Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit
    Description
    1/3 radius bone mineral density was measured in a subset of participants by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
    Time Frame
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    Title
    Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit
    Description
    Lumbar spine bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Time Frame
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    Title
    Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit
    Description
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Time Frame
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    Title
    Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit
    Description
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Time Frame
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    Title
    Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit
    Description
    1/3 radius BMD was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Measurements at some time points during the core study 20030216 were only taken in a subset of participants.
    Time Frame
    Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
    Title
    Number of Participants With New Vertebral Fractures
    Description
    A new vertebral fracture, assessed by lateral spine X-ray using Genant semiquantitative scoring method, was identified as an ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4, excluding any fracture associated with high trauma severity or a pathologic fracture.
    Time Frame
    84 months
    Title
    Number of Participants With Non-Vertebral Fractures
    Description
    Non-vertebral fractures (osteoporotic) were defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging (MRI) confirming the fracture, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
    Time Frame
    84 months
    Title
    Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
    Description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Time Frame
    Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    Title
    Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit
    Description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new sparticipants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Time Frame
    Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    Title
    Percent Change From Study 20030216 Baseline in CTX-1 by Visit
    Description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Time Frame
    Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    Title
    Percent Change From Study 20030216 Baseline in P1NP by Visit
    Description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    Time Frame
    Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    Title
    Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
    Time Frame
    Baseline (of extension study) and day 10
    Title
    Serum Denosumab Concentration
    Description
    Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 0.8 ng/mL. Values of 0 in the table below indicate data below the lower limit of quantification.
    Time Frame
    Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
    Title
    Bone Histomorphometry: Cancellous Bone Volume
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by quantitative histomorphometry.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Trabecular Number
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular number is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Trabecular number is a measure of trabecular connectivity and decreases with bone loss.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Trabecular Separation
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular separation is the mean distance between trabeculae (measured by integrated computer graphics). Trabecular separation increases with trabecular bone loss.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Trabecular Thickness
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Mean trabecular thickness is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Trabecular thickness is reduced by aging and osteoporosis.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Cortical Width
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by tartrate-resistant acid phosphatase (TRAP) staining histomorphometry.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Surface Density
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoblast - Osteoid Interface
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoid Surface
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoid Thickness
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid thickness (width) is the mean thickness of osteoid seams on cancellous surfaces. Osteoid thickness is normally <12.5 µm. Increased osteoid thickness suggests abnormal mineralization (osteomalacia).
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Wall Thickness
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Wall thickness is the average thickness of trabecular bone structural units (BSU) and is used to assess the overall balance between resorption and formation.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Eroded Surface/Bone Surface
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Eroded surface/bone surface is the percentage of bone surface occupied by eroded (resorption) cavities (Howships lacunae), with or without osteoclasts.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoclast Number - Length Based
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per mm of bone.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoclast Number - Surface Based
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per 100 mm of bone surface area.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per mm of bone.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per 100 mm of bone surface. Da
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Single-label Surface
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. A single label is deposited if formation either started or ended during the interval between the uses of the two courses of tetracycline administration. Single-label surface is expressed as a percentage of total bone surface.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Double-label Surface
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The presence of double labels indicates that normal bone mineralization was actively occurring over the entire labeling interval. Double-label surface is expressed as a percentage of total bone surface.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Mineralizing Surface
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Mineral Apposition Rate
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. MAR is calculated as the average distance between visible labels, divided by the labeling interval.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Adjusted Apposition Rate
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the average rate at which new bone mineral is being added on any actively forming surface. Adjusted MAR is calculated as: (average distance between visible labels / labeling interval) * (total mineralizing surface/total bone surface).
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Bone Formation Rate - Surface Based
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - surface based is the calculated rate at which cancellous bone surface is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone surface).
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Bone Formation Rate - Volume Based
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - volume based is the calculated rate at which cancellous bone volume is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone volume).
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Formation Period
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Formation period (FP) is the mean time required to rebuild a new bone structural unit or osteon from the cement line back to the bone surface at a single location, and is given by wall width / adjusted apposition rate.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Activation Frequency
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The average time that it takes for a new remodeling cycle to begin on any point on a cancellous surface is called the activation frequency. Activation frequency is calculated as the bone formation rate / wall width.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Osteoid Volume
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid volume is the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).
    Time Frame
    Month 24 and month 84
    Title
    Bone Histomorphometry: Mineralization Lag Time
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Mineralization lag time is the average time interval between osteoid formation and its subsequent mineralization and is calculated by dividing the osteoid width by the apposition rate.
    Time Frame
    Month 24 and month 84
    Title
    Bone Histology at Month 24
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.
    Time Frame
    Month 24
    Title
    Bone Histology at Month 84
    Description
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.
    Time Frame
    Month 84

    10. Eligibility

    Sex
    Female
    Minimum Age & Unit of Time
    60 Years
    Maximum Age & Unit of Time
    94 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Postmenopausal women who have attended the 20030216 (NCT00089791) study month 36 visit will be eligible to participate if they meet the inclusion and exclusion criteria given below. Inclusion Criteria Subjects must sign the informed consent before any study specific procedures are performed and agree to receive denosumab 60 mg subcutaneous injection every 6 months Subjects must not have discontinued investigational product during the 20030216 study and must have attended the 20030216 study month 36 visit Subjects must be re-consented prior to (or at) the 24 month visit for participation beyond month 24. Exclusion Criteria Permanently non-ambulatory subjects (use of an assistive device eg, cane, walker, etc. is permitted) Missed 2 or more investigational product doses during the 20030216 study Any disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures Developed sensitivity to mammalian cell derived drug products during the 20030216 study Unable to tolerate calcium supplementation during the last 6 months of participation in the 20030216 study (between the month 30 and month 36 20030216 study visits) Currently receiving any investigational product other than denosumab or having received any investigational product during the 20030216 study Current use of the following osteoporosis agents: bisphosphonates, calcitonin, fluoride, parathyroid hormone, selective estrogen receptor modulators, systemic oral or transdermal estrogen (except vaginal preparations and estrogen creams which are acceptable), strontium, or tibolone For bone biopsy sub-study subjects only: known or suspected sensitivity or contraindication to tetracycline derivatives
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    MD
    Organizational Affiliation
    Amgen
    Official's Role
    Study Director

    12. IPD Sharing Statement

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    Links:
    URL
    http://www.amgentrials.com
    Description
    AmgenTrials clinical trials website

    Learn more about this trial

    Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis

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