OsteopeniaPhase 3NCT00523341
Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis
A Phase 3 study testing Denosumab in people with Osteopenia and Osteoporosis, run by Amgen.
Trial 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. Read more about this study
- Who is it for?
- Ages 60 to 94 years, women only
- Conditions the study is for
- Osteopenia, Osteoporosis
- What is being tested?
- Denosumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4,550 participants
- Where
- No sites listed yet
- Study dates
- 7 Aug 2007to 19 Jul 2015
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 to 94 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
About this study
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
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.
- Conditions
- Osteopenia, Osteoporosis
- Being tested
- Denosumab
- Keywords
- postmenopausal osteoporosis, low bone density, fractures, low bone mass
- Medical subject headings
- Bone Diseases, Metabolic, Osteoporosis, Osteoporosis, Postmenopausal, Fractures, Bone
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DenosumabBiological
Also called AMG 162, Prolia
Administered by subcutaneous injection once every 6 months.
| Study group | Role | What they receive |
|---|---|---|
| Denosumab | Experimental | Participants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years. Receives: Biological: Denosumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 84 months
Number of Participants With Antibodies to Denosumab
Measured: Every 12 months through Month 84
Secondary outcomes (45)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Month 84
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Aug 2007 (estimated)
- Study start7 Aug 2007
- Primary completion19 Jul 2015
- Study completion19 Jul 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for OsteopeniaStudies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 4,550 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00523341
- Sponsor's protocol ID
- 20060289
- Status last verified
- Nov 2022
- First submitted
- 30 Aug 2007
- Last updated
- 7 Nov 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Torring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.
PubMed 29105841Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S, Valter I, Wagman RB, Yin X, Yue SV, Boivin G. Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2498-2509. doi: 10.1210/jc.2017-02669.
PubMed 29672714Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwinski E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017 Jul;5(7):513-523. doi: 10.1016/S2213-8587(17)30138-9. Epub 2017 May 22.
PubMed 28546097Ferrari S, Eastell R, Napoli N, Schwartz A, Hofbauer LC, Chines A, Wang A, Pannacciulli N, Cummings SR. Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension. Bone. 2020 May;134:115268. doi: 10.1016/j.bone.2020.115268. Epub 2020 Feb 10.
PubMed 32058020Ferrari S, Lewiecki EM, Butler PW, Kendler DL, Napoli N, Huang S, Crittenden DB, Pannacciulli N, Siris E, Binkley N. Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed. Bone. 2020 May;134:115287. doi: 10.1016/j.bone.2020.115287. Epub 2020 Feb 21.
PubMed 32092479Kendler DL, Chines A, Brandi ML, Papapoulos S, Lewiecki EM, Reginster JY, Munoz Torres M, Wang A, Bone HG. The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporos Int. 2019 Jan;30(1):71-78. doi: 10.1007/s00198-018-4687-2. Epub 2018 Sep 22.
PubMed 30244369Watts NB, Brown JP, Papapoulos S, Lewiecki EM, Kendler DL, Dakin P, Wagman RB, Wang A, Daizadeh NS, Smith S, Bone HG. Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. J Bone Miner Res. 2017 Jul;32(7):1481-1485. doi: 10.1002/jbmr.3119. Epub 2017 Apr 3.
PubMed 28277603Watts NB, Grbic JT, Binkley N, Papapoulos S, Butler PW, Yin X, Tierney A, Wagman RB, McClung M. Invasive Oral Procedures and Events in Postmenopausal Women With Osteoporosis Treated With Denosumab for Up to 10 Years. J Clin Endocrinol Metab. 2019 Jun 1;104(6):2443-2452. doi: 10.1210/jc.2018-01965.
PubMed 30759221Adachi JD, Bone HG, Daizadeh NS, Dakin P, Papapoulos S, Hadji P, Recknor C, Bolognese MA, Wang A, Lin CJF, Wagman RB, Ferrari S. Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study. BMC Musculoskelet Disord. 2017 Apr 27;18(1):174. doi: 10.1186/s12891-017-1520-6.
PubMed 28449657Bilezikian JP, Lin CJF, Brown JP, Wang AT, Yin X, Ebeling PR, Fahrleitner-Pammer A, Franek E, Gilchrist N, Miller PD, Simon JA, Valter I, Zerbini CAF, Libanati C, Chines A. Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group. Osteoporos Int. 2019 Sep;30(9):1855-1864. doi: 10.1007/s00198-019-05020-8. Epub 2019 Jun 14.
PubMed 31201481Ferrari S, Butler PW, Kendler DL, Miller PD, Roux C, Wang AT, Huang S, Wagman RB, Lewiecki EM. Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3450-3461. doi: 10.1210/jc.2019-00271.
PubMed 31125092Ferrari S, Libanati C, Lin CJF, Brown JP, Cosman F, Czerwinski E, de Gregomicronrio LH, Malouf-Sierra J, Reginster JY, Wang A, Wagman RB, Lewiecki EM. Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment. J Bone Miner Res. 2019 Jun;34(6):1033-1040. doi: 10.1002/jbmr.3722. Epub 2019 May 29.
PubMed 30919997Broadwell A, Chines A, Ebeling PR, Franek E, Huang S, Smith S, Kendler D, Messina O, Miller PD. Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease. J Clin Endocrinol Metab. 2021 Jan 23;106(2):397-409. doi: 10.1210/clinem/dgaa851.
PubMed 33211870Cosman F, Huang S, McDermott M, Cummings SR. Multiple Vertebral Fractures After Denosumab Discontinuation: FREEDOM and FREEDOM Extension Trials Additional Post Hoc Analyses. J Bone Miner Res. 2022 Nov;37(11):2112-2120. doi: 10.1002/jbmr.4705. Epub 2022 Oct 12.
PubMed 36088628Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Mellstrom D, Radominski SC, Reginster JY, Resch H, Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013 Nov;98(11):4483-92. doi: 10.1210/jc.2013-1597. Epub 2013 Aug 26.
PubMed 23979955
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00523341
- Acronym / sponsor ID
- 20060289
- Conditions
- Osteopenia, Osteoporosis
- Keywords
- postmenopausal osteoporosis, low bone density, fractures, low bone mass
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 4,550 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Study start
- 7 Aug 2007 (actual)
- Primary completion
- 19 Jul 2015 (actual)
- Study completion
- 19 Jul 2015 (actual)
- First posted
- 31 Aug 2007 (estimated)
- Results
- Posted 12 Jul 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Denosumab | Experimental | Biological: DenosumabParticipants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years. |
Who may qualify
- Ages
- 60 to 94 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (8 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DenosumabAlso: AMG 162, ProliaAdministered by subcutaneous injection once every 6 months. | Biological | Denosumab |
Primary outcome
Number of Participants With Adverse Events (AEs)
Time frame: 84 months
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
Time frame: 84 months
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
Time frame: Every 12 months through Month 84
45 secondary outcomes
Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
Time frame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
Time frame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
Number of Participants With New Vertebral Fractures
Time frame: 84 months
Number of Participants With Non-Vertebral Fractures
Time frame: 84 months
Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline (of extension study) and day 10
Serum Denosumab Concentration
Time frame: Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
Bone Histomorphometry: Cancellous Bone Volume
Time frame: Month 24 and month 84
Bone Histomorphometry: Trabecular Number
Time frame: Month 24 and month 84
Bone Histomorphometry: Trabecular Separation
Time frame: Month 24 and month 84
Bone Histomorphometry: Trabecular Thickness
Time frame: Month 24 and month 84
Bone Histomorphometry: Cortical Width
Time frame: Month 24 and month 84
Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
Time frame: Month 24 and month 84
Bone Histomorphometry: Surface Density
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoblast - Osteoid Interface
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoid Surface
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoid Thickness
Time frame: Month 24 and month 84
Bone Histomorphometry: Wall Thickness
Time frame: Month 24 and month 84
Bone Histomorphometry: Eroded Surface/Bone Surface
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number - Length Based
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number - Surface Based
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
Time frame: Month 24 and month 84
Bone Histomorphometry: Single-label Surface
Time frame: Month 24 and month 84
Bone Histomorphometry: Double-label Surface
Time frame: Month 24 and month 84
Bone Histomorphometry: Mineralizing Surface
Time frame: Month 24 and month 84
Bone Histomorphometry: Mineral Apposition Rate
Time frame: Month 24 and month 84
Bone Histomorphometry: Adjusted Apposition Rate
Time frame: Month 24 and month 84
Bone Histomorphometry: Bone Formation Rate - Surface Based
Time frame: Month 24 and month 84
Bone Histomorphometry: Bone Formation Rate - Volume Based
Time frame: Month 24 and month 84
Bone Histomorphometry: Formation Period
Time frame: Month 24 and month 84
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 29105841Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Torring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.
- Background: PubMed 29672714Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S, Valter I, Wagman RB, Yin X, Yue SV, Boivin G. Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2498-2509. doi: 10.1210/jc.2017-02669.
- Background: PubMed 28546097Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwinski E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017 Jul;5(7):513-523. doi: 10.1016/S2213-8587(17)30138-9. Epub 2017 May 22.
- Background: PubMed 32058020Ferrari S, Eastell R, Napoli N, Schwartz A, Hofbauer LC, Chines A, Wang A, Pannacciulli N, Cummings SR. Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension. Bone. 2020 May;134:115268. doi: 10.1016/j.bone.2020.115268. Epub 2020 Feb 10.
- Background: PubMed 32092479Ferrari S, Lewiecki EM, Butler PW, Kendler DL, Napoli N, Huang S, Crittenden DB, Pannacciulli N, Siris E, Binkley N. Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed. Bone. 2020 May;134:115287. doi: 10.1016/j.bone.2020.115287. Epub 2020 Feb 21.
- Background: PubMed 30244369Kendler DL, Chines A, Brandi ML, Papapoulos S, Lewiecki EM, Reginster JY, Munoz Torres M, Wang A, Bone HG. The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporos Int. 2019 Jan;30(1):71-78. doi: 10.1007/s00198-018-4687-2. Epub 2018 Sep 22.
- Background: PubMed 28277603Watts NB, Brown JP, Papapoulos S, Lewiecki EM, Kendler DL, Dakin P, Wagman RB, Wang A, Daizadeh NS, Smith S, Bone HG. Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. J Bone Miner Res. 2017 Jul;32(7):1481-1485. doi: 10.1002/jbmr.3119. Epub 2017 Apr 3.
- Background: PubMed 30759221Watts NB, Grbic JT, Binkley N, Papapoulos S, Butler PW, Yin X, Tierney A, Wagman RB, McClung M. Invasive Oral Procedures and Events in Postmenopausal Women With Osteoporosis Treated With Denosumab for Up to 10 Years. J Clin Endocrinol Metab. 2019 Jun 1;104(6):2443-2452. doi: 10.1210/jc.2018-01965.
- Background: PubMed 28449657Adachi JD, Bone HG, Daizadeh NS, Dakin P, Papapoulos S, Hadji P, Recknor C, Bolognese MA, Wang A, Lin CJF, Wagman RB, Ferrari S. Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study. BMC Musculoskelet Disord. 2017 Apr 27;18(1):174. doi: 10.1186/s12891-017-1520-6.
- Background: PubMed 31201481Bilezikian JP, Lin CJF, Brown JP, Wang AT, Yin X, Ebeling PR, Fahrleitner-Pammer A, Franek E, Gilchrist N, Miller PD, Simon JA, Valter I, Zerbini CAF, Libanati C, Chines A. Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group. Osteoporos Int. 2019 Sep;30(9):1855-1864. doi: 10.1007/s00198-019-05020-8. Epub 2019 Jun 14.
- Background: PubMed 31125092Ferrari S, Butler PW, Kendler DL, Miller PD, Roux C, Wang AT, Huang S, Wagman RB, Lewiecki EM. Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3450-3461. doi: 10.1210/jc.2019-00271.
- Background: PubMed 30919997Ferrari S, Libanati C, Lin CJF, Brown JP, Cosman F, Czerwinski E, de Gregomicronrio LH, Malouf-Sierra J, Reginster JY, Wang A, Wagman RB, Lewiecki EM. Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment. J Bone Miner Res. 2019 Jun;34(6):1033-1040. doi: 10.1002/jbmr.3722. Epub 2019 May 29.
- AmgenTrials clinical trials websiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Denosumab in people with Osteopenia and Osteoporosis, run by Amgen.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jul 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Adverse Events (AEs) (time frame: 84 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00523341, which also lists 16 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2022.