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

Study Overview
=================
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.

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

Conditions
-----------------
Osteopenia, Osteoporosis

Intervention / Treatment
-----------------
* Biological: Denosumab


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 94 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br>Participants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years. | Biological: Denosumab<br>* Administered by subcutaneous injection once every 6 months.<br>* Other names: Prolia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 84 months | 
| 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. | 84 months | 
| Number of Participants With Antibodies to Denosumab |  | Every 12 months through Month 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | 
| 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. | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | 
| 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. | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | 
| 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. | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | 
| 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. | Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84 | 
| 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. | Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84 | 
| 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. | Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84 | 
| 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. | Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84 | 
| 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. | 84 months | 
| 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. | 84 months | 
| 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. | Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 
| 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. | Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 
| 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. | Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 
| 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. | Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 
| Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10 |  | Baseline (of extension study) and 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. | Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose) | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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). | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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 | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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). | Month 24 and month 84 | 
| 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). | Month 24 and month 84 | 
| 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). | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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). | Month 24 and month 84 | 
| 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. | Month 24 and month 84 | 
| 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. | Month 24 | 
| 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. | Month 84 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
postmenopausal osteoporosis, low bone density, fractures, low bone mass