Osteopenia, Osteoporosis
Conditions
Keywords
postmenopausal osteoporosis, low bone density, fractures, low bone mass
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.
Interventions
BIOLOGICALDenosumab
Administered by subcutaneous injection once every 6 months.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
60 Years to 94 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | 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 | 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 | Every 12 months through Month 84 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | 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 | Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84 | 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 | Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84 | 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 | Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84 | 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 | Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84 | 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 | 84 months | 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 | 84 months | 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 | Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 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 | Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 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 | Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 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 | Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84 | 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 | Baseline (of extension study) and day 10 | — |
| Serum Denosumab Concentration | Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose) | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 Volume | Month 24 and month 84 | 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: Osteoid Thickness | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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 | Month 24 and month 84 | 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. |
| Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Bone Histomorphometry: Mineralization Lag Time | Month 24 and month 84 | 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 | 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 | 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. |
| Bone Histomorphometry: Activation Frequency | Month 24 and month 84 | 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. |
| Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | 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 | Baseline (of extension study) and months 12, 24, 36, 60 and 84 | Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
Participant flow
Recruitment details
This was an extension study open to participants who had completed core study 20030216 (NCT00089791). The study was conducted at 178 centers in North America, South America, Europe, Australia, and New Zealand. Participants were enrolled from 7 August 2007 to 20 June 2008.
Pre-assignment details
All participants received open-label denosumab during this study. Results are reported by the Study 20030216 randomized treatment groups (placebo versus denosumab).
Participants by arm
| Arm | Count |
|---|---|
| Placebo / Denosumab Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study. | 2,207 |
| Denosumab / Denosumab Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment). | 2,343 |
| Total | 4,550 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 122 | 155 |
| Overall Study | Death | 101 | 110 |
| Overall Study | Disease Progression | 1 | 0 |
| Overall Study | Ineligibility Determined | 3 | 4 |
| Overall Study | Lost to Follow-up | 73 | 61 |
| Overall Study | Non-compliance | 20 | 13 |
| Overall Study | Other | 181 | 198 |
| Overall Study | Physician Decision | 14 | 13 |
| Overall Study | Protocol Deviation | 6 | 5 |
| Overall Study | Requirement for Alternative Therapy | 4 | 14 |
| Overall Study | Withdrawal by Subject | 399 | 427 |
Baseline characteristics
| Characteristic | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| Age, Continuous | 74.8 years STANDARD_DEVIATION 5.1 | 74.9 years STANDARD_DEVIATION 5 | 74.8 years STANDARD_DEVIATION 5 |
| Age, Customized 60 - 64 years | 58 participants | 49 participants | 107 participants |
| Age, Customized 65 - 69 years | 326 participants | 320 participants | 646 participants |
| Age, Customized 70 - 74 years | 672 participants | 716 participants | 1388 participants |
| Age, Customized ≥ 75 years | 1151 participants | 1258 participants | 2409 participants |
| Any Historical Fracture at Age ≥ 55 Years | 1089 participants | 1133 participants | 2222 participants |
| Bone Mineral Density T-score Femoral neck | -2.17 T-score STANDARD_DEVIATION 0.72 | -1.83 T-score STANDARD_DEVIATION 0.75 | -1.99 T-score STANDARD_DEVIATION 0.75 |
| Bone Mineral Density T-score Lumbar spine | -2.81 T-score STANDARD_DEVIATION 0.75 | -2.14 T-score STANDARD_DEVIATION 0.8 | -2.47 T-score STANDARD_DEVIATION 0.84 |
| Bone Mineral Density T-score Total hip | -1.93 T-score STANDARD_DEVIATION 0.8 | -1.50 T-score STANDARD_DEVIATION 0.79 | -1.71 T-score STANDARD_DEVIATION 0.83 |
| Bone Mineral Density T-score at Study 20030216 Baseline Femoral neck | -2.11 T-score STANDARD_DEVIATION 0.71 | -2.11 T-score STANDARD_DEVIATION 0.71 | -2.11 T-score STANDARD_DEVIATION 0.71 |
| Bone Mineral Density T-score at Study 20030216 Baseline Lumbar spine | -2.84 T-score STANDARD_DEVIATION 0.68 | -2.83 T-score STANDARD_DEVIATION 0.67 | -2.83 T-score STANDARD_DEVIATION 0.68 |
| Bone Mineral Density T-score at Study 20030216 Baseline Total hip | -1.85 T-score STANDARD_DEVIATION 0.79 | -1.85 T-score STANDARD_DEVIATION 0.79 | -1.85 T-score STANDARD_DEVIATION 0.79 |
| Race/Ethnicity, Customized Asian | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized Black | 16 participants | 19 participants | 35 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 121 participants | 145 participants | 266 participants |
| Race/Ethnicity, Customized Japanese | 3 participants | 5 participants | 8 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 2063 participants | 2169 participants | 4232 participants |
| Sex: Female, Male Female | 2207 Participants | 2343 Participants | 4550 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,809 / 2,206 | 1,920 / 2,343 |
| serious Total, serious adverse events | 945 / 2,206 | 1,014 / 2,343 |
Outcome results
Primary
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.
Time frame: 84 months
Population: All participants who received at least one dose of denosumab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Serious adverse event | 945 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Any adverse event (AE) | 2070 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Fatal adverse event | 101 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | AE leading to study discontinuation | 145 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | AE leading to discontinuation of denosumab | 184 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAE) | 185 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse events | 26 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Fatal treatment-related adverse events | 1 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | TRAE leading to study discontinuation | 16 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of denosumab | 30 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Positively adjudicated osteonecrosis of the jaw | 6 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Positively adjudicated atypical femoral fracture | 1 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Hypocalcaemia | 10 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | AEs potentially related to hypersensitivity | 260 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Serious infections | 161 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Serious bacterial cellulitis | 7 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Malignancy | 227 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Cardiac disorders | 449 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Vascular disorders | 693 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Fracture healing complications | 0 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Eczema | 99 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Acute pancreatitis | 4 participants |
| Placebo / Denosumab | Number of Participants With Adverse Events (AEs) | Musculoskeletal pain | 1125 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Malignancy | 237 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Musculoskeletal pain | 1206 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Positively adjudicated atypical femoral fracture | 1 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Any adverse event (AE) | 2173 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Serious adverse event | 1014 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Fracture healing complications | 1 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Fatal adverse event | 108 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Hypocalcaemia | 6 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | AE leading to study discontinuation | 173 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Cardiac disorders | 492 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | AE leading to discontinuation of denosumab | 216 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | AEs potentially related to hypersensitivity | 280 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAE) | 188 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Acute pancreatitis | 8 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse events | 28 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Serious infections | 185 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Fatal treatment-related adverse events | 0 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Vascular disorders | 732 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | TRAE leading to study discontinuation | 9 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Serious bacterial cellulitis | 12 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of denosumab | 25 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Eczema | 115 participants |
| Denosumab / Denosumab | Number of Participants With Adverse Events (AEs) | Positively adjudicated osteonecrosis of the jaw | 7 participants |
Primary
Number of Participants With Antibodies to Denosumab
Time frame: Every 12 months through Month 84
Population: All participants who received at least 1 dose of denosumab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo / Denosumab | Number of Participants With Antibodies to Denosumab | 1 participants |
| Denosumab / Denosumab | Number of Participants With Antibodies to Denosumab | 0 participants |
Primary
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.
Time frame: 84 months
Population: All participants who received at least 1 dose of denosumab
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low sodium - Grade 3 | 28 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High calcium - Grade 3 | 2 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High calcium - Grade 4 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High corrected calcium - Grade 3 | 2 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low glucose - Grade 4 | 1 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low white blood cells - Grade 4 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low sodium - Grade 4 | 1 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High potassium - Grade 3 | 9 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High potassium - Grade 4 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low potassium - Grade 3 | 7 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low magnesium - Grade 3 | 1 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low magnesium - Grade 4 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High corrected calcium - Grade 4 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low phosphorus - Grade 3 | 3 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High Creatinine - Grade 3 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High aspartate amino transferase (AST) - Grade 3 | 5 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High aspartate amino transferase (AST) - Grade 4 | 1 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High alanine amino transferase (ALT) - Grade 3 | 8 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High alanine amino transferase (ALT) - Grade 4 | 1 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High total bilirubin - Grade 3 | 2 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low albumin - Grade 3 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High glucose - Grade 3 | 35 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High glucose - Grade 4 | 0 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low glucose - Grade 3 | 4 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low hemoglobin - Grade 3 | 6 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low platelets - Grade 3 | 3 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low platelets - Grade 4 | 2 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low white blood cells - Grade 3 | 5 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low lymphocytes - Grade 3 | 17 participants |
| Placebo / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low lymphocytes - Grade 4 | 2 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High Creatinine - Grade 3 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low sodium - Grade 3 | 25 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low magnesium - Grade 4 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low platelets - Grade 3 | 7 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High calcium - Grade 3 | 3 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High aspartate amino transferase (AST) - Grade 3 | 11 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High calcium - Grade 4 | 2 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High glucose - Grade 4 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High aspartate amino transferase (AST) - Grade 4 | 0 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low glucose - Grade 4 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low white blood cells - Grade 3 | 7 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low lymphocytes - Grade 4 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low white blood cells - Grade 4 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High alanine amino transferase (ALT) - Grade 3 | 10 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low sodium - Grade 4 | 0 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low glucose - Grade 3 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High potassium - Grade 3 | 11 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High alanine amino transferase (ALT) - Grade 4 | 0 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High potassium - Grade 4 | 3 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low platelets - Grade 4 | 4 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low potassium - Grade 3 | 7 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High total bilirubin - Grade 3 | 3 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low magnesium - Grade 3 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low hemoglobin - Grade 3 | 4 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High corrected calcium - Grade 3 | 3 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low albumin - Grade 3 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High corrected calcium - Grade 4 | 2 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low lymphocytes - Grade 3 | 16 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | Low phosphorus - Grade 3 | 1 participants |
| Denosumab / Denosumab | Number of Participants With Laboratory Toxicities of Grade ≥ 3 | High glucose - Grade 3 | 37 participants |
Secondary
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.
Time frame: Month 24
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 bone biopsy evaluable for histology at extension month 24.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo / Denosumab | Bone Histology at Month 24 | Normal lamellar bone | 13 biopsies |
| Placebo / Denosumab | Bone Histology at Month 24 | Normal mineralization | 13 biopsies |
| Placebo / Denosumab | Bone Histology at Month 24 | Osteoid | 13 biopsies |
| Placebo / Denosumab | Bone Histology at Month 24 | Osteomalacia | 0 biopsies |
| Placebo / Denosumab | Bone Histology at Month 24 | Marrow fibrosis | 0 biopsies |
| Placebo / Denosumab | Bone Histology at Month 24 | Woven bone | 0 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 24 | Marrow fibrosis | 0 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 24 | Normal lamellar bone | 28 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 24 | Osteomalacia | 0 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 24 | Normal mineralization | 28 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 24 | Woven bone | 0 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 24 | Osteoid | 23 biopsies |
Secondary
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.
Time frame: Month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 bone biopsy evaluable for histology at extension month 84.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Denosumab / Denosumab | Bone Histology at Month 84 | Normal lamellar bone | 22 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 84 | Normal mineralization | 22 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 84 | Osteoid | 18 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 84 | Osteomalacia | 0 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 84 | Marrow fibrosis | 0 biopsies |
| Denosumab / Denosumab | Bone Histology at Month 84 | Woven bone | 0 biopsies |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available activation frequency data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Activation Frequency | Month 24 (n = 5, 10) | 0.022 /year | Standard Deviation 0.019 |
| Placebo / Denosumab | Bone Histomorphometry: Activation Frequency | Month 84 (n = 0, 10) | NA /year | — |
| Denosumab / Denosumab | Bone Histomorphometry: Activation Frequency | Month 24 (n = 5, 10) | 0.045 /year | Standard Deviation 0.049 |
| Denosumab / Denosumab | Bone Histomorphometry: Activation Frequency | Month 84 (n = 0, 10) | 0.014 /year | Standard Deviation 0.024 |
Secondary
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).
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available adjusted apposition rate data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Adjusted Apposition Rate | Month 24 (n = 5, 9) | 0.394 μm/day | Standard Deviation 0.471 |
| Placebo / Denosumab | Bone Histomorphometry: Adjusted Apposition Rate | Month 84 (n = 0, 10) | NA μm/day | — |
| Denosumab / Denosumab | Bone Histomorphometry: Adjusted Apposition Rate | Month 24 (n = 5, 9) | 0.517 μm/day | Standard Deviation 0.537 |
| Denosumab / Denosumab | Bone Histomorphometry: Adjusted Apposition Rate | Month 84 (n = 0, 10) | 0.818 μm/day | Standard Deviation 1.207 |
Secondary
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).
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Bone Formation Rate - Surface Based | Month 24 (n = 5, 10) | 0.898 μm³/μm²/year | Standard Deviation 0.706 |
| Placebo / Denosumab | Bone Histomorphometry: Bone Formation Rate - Surface Based | Month 84 (n = 0, 10) | NA μm³/μm²/year | — |
| Denosumab / Denosumab | Bone Histomorphometry: Bone Formation Rate - Surface Based | Month 24 (n = 5, 10) | 2.153 μm³/μm²/year | Standard Deviation 2.468 |
| Denosumab / Denosumab | Bone Histomorphometry: Bone Formation Rate - Surface Based | Month 84 (n = 0, 10) | 0.691 μm³/μm²/year | Standard Deviation 0.868 |
Secondary
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).
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Bone Formation Rate - Volume Based | Month 24 (n = 5, 10) | 1.454 percent of bone volume per year | Standard Deviation 1.265 |
| Placebo / Denosumab | Bone Histomorphometry: Bone Formation Rate - Volume Based | Month 84 (n = 0, 10) | NA percent of bone volume per year | — |
| Denosumab / Denosumab | Bone Histomorphometry: Bone Formation Rate - Volume Based | Month 24 (n = 5, 10) | 3.162 percent of bone volume per year | Standard Deviation 3.773 |
| Denosumab / Denosumab | Bone Histomorphometry: Bone Formation Rate - Volume Based | Month 84 (n = 0, 10) | 1.071 percent of bone volume per year | Standard Deviation 1.308 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Cancellous Bone Volume | Month 24 (n = 13, 25) | 15.253 percentage of total bone tissue volume | Standard Deviation 6.065 |
| Placebo / Denosumab | Bone Histomorphometry: Cancellous Bone Volume | Month 84 (n = 0, 19) | NA percentage of total bone tissue volume | — |
| Denosumab / Denosumab | Bone Histomorphometry: Cancellous Bone Volume | Month 24 (n = 13, 25) | 14.640 percentage of total bone tissue volume | Standard Deviation 6.979 |
| Denosumab / Denosumab | Bone Histomorphometry: Cancellous Bone Volume | Month 84 (n = 0, 19) | 16.358 percentage of total bone tissue volume | Standard Deviation 4.438 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry | Month 84 (n = 0, 19) | NA percentage of total bone tissue volume | — |
| Placebo / Denosumab | Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry | Month 24 (n = 13, 25) | 16.678 percentage of total bone tissue volume | Standard Deviation 7.27 |
| Denosumab / Denosumab | Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry | Month 24 (n = 13, 25) | 15.606 percentage of total bone tissue volume | Standard Deviation 6.986 |
| Denosumab / Denosumab | Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry | Month 84 (n = 0, 19) | 17.631 percentage of total bone tissue volume | Standard Deviation 4.387 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cortical width data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Cortical Width | Month 24 (n = 13, 28) | 622.22 μm | Standard Deviation 246.7 |
| Placebo / Denosumab | Bone Histomorphometry: Cortical Width | Month 84 (n = 0, 21) | NA μm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Cortical Width | Month 24 (n = 13, 28) | 707.69 μm | Standard Deviation 237.97 |
| Denosumab / Denosumab | Bone Histomorphometry: Cortical Width | Month 84 (n = 0, 21) | 786.19 μm | Standard Deviation 279.81 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available double-label surface data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Double-label Surface | Month 24 (n = 5, 10) | 0.258 percentage of bone surface | Standard Deviation 0.207 |
| Placebo / Denosumab | Bone Histomorphometry: Double-label Surface | Month 84 (n = 0, 10) | NA percentage of bone surface | — |
| Denosumab / Denosumab | Bone Histomorphometry: Double-label Surface | Month 24 (n = 5, 10) | 0.356 percentage of bone surface | Standard Deviation 0.295 |
| Denosumab / Denosumab | Bone Histomorphometry: Double-label Surface | Month 84 (n = 0, 10) | 0.106 percentage of bone surface | Standard Deviation 0.237 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available eroded surface/bone surface data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Eroded Surface/Bone Surface | Month 24 (n = 13, 25) | 0.414 percentage of bone surface | Standard Deviation 0.701 |
| Placebo / Denosumab | Bone Histomorphometry: Eroded Surface/Bone Surface | Month 84 (n = 0, 19) | NA percentage of bone surface | — |
| Denosumab / Denosumab | Bone Histomorphometry: Eroded Surface/Bone Surface | Month 24 (n = 13, 25) | 0.328 percentage of bone surface | Standard Deviation 0.613 |
| Denosumab / Denosumab | Bone Histomorphometry: Eroded Surface/Bone Surface | Month 84 (n = 0, 19) | 0.511 percentage of bone surface | Standard Deviation 0.579 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available formation period data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Formation Period | Month 24 (n = 5, 10) | 593.5 days | Standard Deviation 996.8 |
| Placebo / Denosumab | Bone Histomorphometry: Formation Period | Month 84 (n = 0, 10) | NA days | — |
| Denosumab / Denosumab | Bone Histomorphometry: Formation Period | Month 24 (n = 5, 10) | 287.3 days | Standard Deviation 391.5 |
| Denosumab / Denosumab | Bone Histomorphometry: Formation Period | Month 84 (n = 0, 10) | 229.7 days | Standard Deviation 512 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineral apposition rate data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Mineral Apposition Rate | Month 24 (n = 5, 10) | 0.616 μm/day | Standard Deviation 0.219 |
| Placebo / Denosumab | Bone Histomorphometry: Mineral Apposition Rate | Month 84 (n = 0, 10) | NA μm/day | — |
| Denosumab / Denosumab | Bone Histomorphometry: Mineral Apposition Rate | Month 24 (n = 5, 10) | 0.722 μm/day | Standard Deviation 0.573 |
| Denosumab / Denosumab | Bone Histomorphometry: Mineral Apposition Rate | Month 84 (n = 0, 10) | 0.394 μm/day | Standard Deviation 0.233 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralization lag time data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Mineralization Lag Time | Month 24 (n = 5, 10) | 84.9 days | Standard Deviation 136.8 |
| Placebo / Denosumab | Bone Histomorphometry: Mineralization Lag Time | Month 84 (n = 0, 10) | NA days | — |
| Denosumab / Denosumab | Bone Histomorphometry: Mineralization Lag Time | Month 24 (n = 5, 10) | 54.3 days | Standard Deviation 76.1 |
| Denosumab / Denosumab | Bone Histomorphometry: Mineralization Lag Time | Month 84 (n = 0, 10) | 52.3 days | Standard Deviation 114.5 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralizing surface data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Mineralizing Surface | Month 24 (n = 5, 10) | 0.406 percentage of bone surface | Standard Deviation 0.323 |
| Placebo / Denosumab | Bone Histomorphometry: Mineralizing Surface | Month 84 (n = 0, 10) | NA percentage of bone surface | — |
| Denosumab / Denosumab | Bone Histomorphometry: Mineralizing Surface | Month 24 (n = 5, 10) | 0.681 percentage of bone surface | Standard Deviation 0.453 |
| Denosumab / Denosumab | Bone Histomorphometry: Mineralizing Surface | Month 84 (n = 0, 10) | 0.412 percentage of bone surface | Standard Deviation 0.458 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoblast - osteoid interface data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoblast - Osteoid Interface | Month 24 (n = 13, 25) | 22.124 percentage of osteoid surface | Standard Deviation 34.879 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoblast - Osteoid Interface | Month 84 (n = 0, 19) | NA percentage of osteoid surface | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoblast - Osteoid Interface | Month 24 (n = 13, 25) | 17.813 percentage of osteoid surface | Standard Deviation 28.381 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoblast - Osteoid Interface | Month 84 (n = 0, 19) | 5.951 percentage of osteoid surface | Standard Deviation 15.223 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Length Based | Month 24 (n = 13, 25) | 0.096 1/mm | Standard Deviation 0.134 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Length Based | Month 84 (n = 0, 19) | NA 1/mm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Length Based | Month 24 (n = 13, 25) | 0.110 1/mm | Standard Deviation 0.185 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Length Based | Month 84 (n = 0, 19) | 0.077 1/mm | Standard Deviation 0.107 |
Secondary
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
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based | Month 24 (n = 13, 25) | 9.6 1/100 mm | Standard Deviation 13.4 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based | Month 84 (n = 0, 19) | NA 1/100 mm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based | Month 24 (n = 13, 25) | 11.0 1/100 mm | Standard Deviation 18.5 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based | Month 84 (n = 0, 19) | 7.7 1/100 mm | Standard Deviation 10.7 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number - Length Based | Month 24 (n = 13, 25) | 0.086 1/mm | Standard Deviation 0.119 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number - Length Based | Month 84 (n = 0, 19) | NA 1/mm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number - Length Based | Month 24 (n = 13, 25) | 0.107 1/mm | Standard Deviation 0.198 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number - Length Based | Month 84 (n = 0, 19) | 0.074 1/mm | Standard Deviation 0.101 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number - Surface Based | Month 24 (n = 13, 25) | 8.6 1/100 mm | Standard Deviation 11.9 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoclast Number - Surface Based | Month 84 (n = 0, 19) | NA 1/100 mm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number - Surface Based | Month 24 (n = 13, 25) | 10.7 1/100 mm | Standard Deviation 19.8 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoclast Number - Surface Based | Month 84 (n = 0, 19) | 7.4 1/100 mm | Standard Deviation 10.1 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid surface data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoid Surface | Month 24 (n = 13, 25) | 0.915 percentage of total bone surface | Standard Deviation 1.382 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoid Surface | Month 84 (n = 0, 19) | NA percentage of total bone surface | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoid Surface | Month 24 (n = 13, 25) | 0.982 percentage of total bone surface | Standard Deviation 2.489 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoid Surface | Month 84 (n = 0, 19) | 0.421 percentage of total bone surface | Standard Deviation 1.068 |
Secondary
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).
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid thickness data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoid Thickness | Month 24 (n = 13, 25) | 5.139 μm | Standard Deviation 3.261 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoid Thickness | Month 84 (n = 0, 19) | NA μm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoid Thickness | Month 24 (n = 13, 25) | 4.548 μm | Standard Deviation 4.973 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoid Thickness | Month 84 (n = 0, 19) | 4.108 μm | Standard Deviation 3.476 |
Secondary
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).
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid volume data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Osteoid Volume | Month 24 (n = 13, 25) | 0.108 percentage of total bone tissue | Standard Deviation 0.193 |
| Placebo / Denosumab | Bone Histomorphometry: Osteoid Volume | Month 84 (n = 0, 19) | NA percentage of total bone tissue | — |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoid Volume | Month 24 (n = 13, 25) | 0.146 percentage of total bone tissue | Standard Deviation 0.382 |
| Denosumab / Denosumab | Bone Histomorphometry: Osteoid Volume | Month 84 (n = 0, 19) | 0.048 percentage of total bone tissue | Standard Deviation 0.133 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available single-label surface data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Single-label Surface | Month 24 (n = 5, 10) | 0.304 percentage of bone surface | Standard Deviation 0.302 |
| Placebo / Denosumab | Bone Histomorphometry: Single-label Surface | Month 84 (n = 0, 10) | NA percentage of bone surface | — |
| Denosumab / Denosumab | Bone Histomorphometry: Single-label Surface | Month 24 (n = 5, 10) | 0.643 percentage of bone surface | Standard Deviation 0.661 |
| Denosumab / Denosumab | Bone Histomorphometry: Single-label Surface | Month 84 (n = 0, 10) | 0.611 percentage of bone surface | Standard Deviation 0.726 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available surface density data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Surface Density | Month 24 (n = 13, 25) | 2.009 mm²/mm³ | Standard Deviation 0.486 |
| Placebo / Denosumab | Bone Histomorphometry: Surface Density | Month 84 (n = 0, 19) | NA mm²/mm³ | — |
| Denosumab / Denosumab | Bone Histomorphometry: Surface Density | Month 24 (n = 13, 25) | 1.807 mm²/mm³ | Standard Deviation 0.486 |
| Denosumab / Denosumab | Bone Histomorphometry: Surface Density | Month 84 (n = 0, 19) | 2.472 mm²/mm³ | Standard Deviation 0.506 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular number data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Trabecular Number | Month 24 (n = 13, 25) | 1.005 1/mm | Standard Deviation 0.242 |
| Placebo / Denosumab | Bone Histomorphometry: Trabecular Number | Month 24 (n = 0, 19) | NA 1/mm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Trabecular Number | Month 24 (n = 13, 25) | 0.904 1/mm | Standard Deviation 0.243 |
| Denosumab / Denosumab | Bone Histomorphometry: Trabecular Number | Month 24 (n = 0, 19) | 1.235 1/mm | Standard Deviation 0.254 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular separation data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Trabecular Separation | Month 24 (n = 13, 25) | 919.693 μm | Standard Deviation 358.238 |
| Placebo / Denosumab | Bone Histomorphometry: Trabecular Separation | Month 84 (n = 0, 19) | NA μm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Trabecular Separation | Month 24 (n = 13, 25) | 1033.416 μm | Standard Deviation 352.259 |
| Denosumab / Denosumab | Bone Histomorphometry: Trabecular Separation | Month 84 (n = 0, 19) | 708.669 μm | Standard Deviation 171.782 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular thickness data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Trabecular Thickness | Month 24 (n = 13, 25) | 153.878 μm | Standard Deviation 51.859 |
| Placebo / Denosumab | Bone Histomorphometry: Trabecular Thickness | Month 84 (n = 0, 19) | NA μm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Trabecular Thickness | Month 24 (n = 13, 25) | 156.335 μm | Standard Deviation 48.567 |
| Denosumab / Denosumab | Bone Histomorphometry: Trabecular Thickness | Month 84 (n = 0, 19) | 132.965 μm | Standard Deviation 28.064 |
Secondary
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.
Time frame: Month 24 and month 84
Population: Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available wall thickness data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Bone Histomorphometry: Wall Thickness | Month 24 (n = 13, 25) | 43.11 μm | Standard Deviation 6.08 |
| Placebo / Denosumab | Bone Histomorphometry: Wall Thickness | Month 84 (n = 0, 19) | NA μm | — |
| Denosumab / Denosumab | Bone Histomorphometry: Wall Thickness | Month 24 (n = 13, 25) | 49.74 μm | Standard Deviation 10.51 |
| Denosumab / Denosumab | Bone Histomorphometry: Wall Thickness | Month 84 (n = 0, 19) | 39.59 μm | Standard Deviation 7.49 |
Secondary
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.
Time frame: 84 months
Population: All participants enrolled in the extension study who have vertebral X-ray assessment at the extension baseline and at least 1 post-extension baseline visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo / Denosumab | Number of Participants With New Vertebral Fractures | 145 participants |
| Denosumab / Denosumab | Number of Participants With New Vertebral Fractures | 149 participants |
Secondary
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.
Time frame: 84 months
Population: All enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo / Denosumab | Number of Participants With Non-Vertebral Fractures | 219 participants |
| Denosumab / Denosumab | Number of Participants With Non-Vertebral Fractures | 172 participants |
Secondary
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.
Time frame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
Population: Participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 60 (n = 59, 84) | 1.8 percent change |
| Placebo / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 84 (n = 39, 56) | 2.2 percent change |
| Placebo / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 12 (n = 114, 134) | 0.3 percent change |
| Placebo / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 24 (n = 108, 127) | 0.2 percent change |
| Placebo / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 36 (n = 73, 93) | 1.3 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 36 (n = 73, 93) | 0.6 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 60 (n = 59, 84) | 1.4 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 24 (n = 108, 127) | 0.2 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 84 (n = 39, 56) | 1.0 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit | Month 12 (n = 114, 134) | 0.6 percent change |
Secondary
Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
Time frame: Baseline (of extension study) and day 10
Population: Participants who had a calcium corrected by albumin measurement within the Day 10 visit window up to May 31, 2008.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo / Denosumab | Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10 | -3.1 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10 | -2.0 percent change |
Secondary
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.
Time frame: Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Population: Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Day 10 (n = 26, 47) | -90 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 36 (n = 68, 81) | -59 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 12 (n = 27, 56) | -75 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 48 (n = 62, 75) | -58 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 6 (n = 30, 56) | -85 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 60 (n = 59, 70) | -65 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 24 (n = 27, 47) | -67 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 72 (n = 56, 62) | -60 percent change |
| Placebo / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 84 (n = 41, 41) | -64 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 72 (n = 56, 62) | -1 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 84 (n = 41, 41) | -6 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Day 10 (n = 26, 47) | -72 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 6 (n = 30, 56) | -26 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 12 (n = 27, 56) | -13 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 24 (n = 27, 47) | 10 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 36 (n = 68, 81) | 2 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 48 (n = 62, 75) | 0 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit | Month 60 (n = 59, 70) | 0 percent change |
Secondary
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.
Time frame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
Population: Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 24 (n = 1918, 2045) | 3.2 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 60 (n = 1439, 1538) | 5.7 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 36 (n = 1475, 1591) | 4.0 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 84 (n = 1200, 1232) | 7.1 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 12 (n = 2029, 2160) | 2.1 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 84 (n = 1200, 1232) | 3.8 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 12 (n = 2029, 2160) | 0.8 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 24 (n = 1918, 2045) | 1.2 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 36 (n = 1475, 1591) | 1.7 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit | Month 60 (n = 1439, 1538) | 2.8 percent change |
Secondary
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.
Time frame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
Population: Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 24 (n = 1935, 2061) | 7.7 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 60 (n = 1472, 1567) | 13.0 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 36 (n = 1497, 1607) | 9.4 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 84 (n = 1223, 1264) | 16.5 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 12 (n = 2040, 2168) | 5.2 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 84 (n = 1223, 1264) | 10.8 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 12 (n = 2040, 2168) | 2.0 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 24 (n = 1935, 2061) | 3.5 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 36 (n = 1497, 1607) | 4.9 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 60 (n = 1472, 1567) | 7.9 percent change |
Secondary
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.
Time frame: Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Population: Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Day 10 (n = 30, 51) | 6 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 12 (n = 26, 56) | -67 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 24 (n = 27, 47) | -63 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 60 (n = 61, 71) | -54 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 84 (n = 48, 50) | -59 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 6 (n = 30, 53) | -71 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 36 (n = 69, 83) | -57 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 48 (n = 61, 73) | -60 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 72 (n = 55, 64) | -50 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 72 (n = 55, 64) | 44 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 6 (n = 30, 53) | -23 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 12 (n = 26, 56) | 7 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 24 (n = 27, 47) | 11 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 48 (n = 61, 73) | 8 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 60 (n = 61, 71) | 30 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 36 (n = 69, 83) | 29 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Month 84 (n = 48, 50) | 32 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit | Day 10 (n = 30, 51) | 14 percent change |
Secondary
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.
Time frame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
Population: Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 24 (n = 1918, 2045) | 4.1 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 60 (n = 1439, 1538) | 6.2 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 36 (n = 1475, 1591) | 4.9 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 84 (n = 1200, 1232) | 7.4 percent change |
| Placebo / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 12 (n = 2029, 2160) | 3.0 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 84 (n = 1200, 1232) | 3.4 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 12 (n = 2029, 2160) | 0.8 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 24 (n = 1918, 2045) | 1.4 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 36 (n = 1475, 1591) | 1.8 percent change |
| Denosumab / Denosumab | Percent Change From Baseline in Total Hip Bone Mineral Density by Visit | Month 60 (n = 1439, 1538) | 2.6 percent change |
Secondary
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.
Time frame: Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
Population: Participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 24 (n = 107, 127) | -1.2 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 60 (n = 59, 83) | 0.3 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 36 (n = 73, 92) | -0.2 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 84 (n = 39, 56) | 0.6 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 12 (n = 113, 133) | -1.0 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 84 (n = 39, 56) | 2.8 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 12 (n = 113, 133) | 2.6 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 24 (n = 107, 127) | 2.1 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 36 (n = 73, 92) | 2.4 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit | Month 60 (n = 59, 83) | 3.3 percent change |
Secondary
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.
Time frame: Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Population: Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 6 (n = 32, 72) | -83 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 36 (n = 289, 313) | -71 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Day 10 (n = 26, 56) | -90 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 48 (n = 274, 290) | -70 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 12 (n = 27, 65) | -77 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 60 (n = 268, 276) | -67 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 84 (n = 217, 216) | -63 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 72 (n = 243, 248) | -69 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 24 (n = 28, 60) | -65 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 84 (n = 217, 216) | -53 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Day 10 (n = 26, 56) | -91 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 6 (n = 32, 72) | -77 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 12 (n = 27, 65) | -63 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 24 (n = 28, 60) | -53 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 36 (n = 289, 313) | -52 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 48 (n = 274, 290) | -61 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 60 (n = 268, 276) | -53 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in CTX-1 by Visit | Month 72 (n = 243, 248) | -59 percent change |
Secondary
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.
Time frame: Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
Population: Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 24 (n = 1895, 2017) | 2.6 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 60 (n = 1424, 1518) | 5.0 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 36 (n = 1457, 1567) | 3.4 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 84 (n = 1189, 1215) | 6.4 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 12 (n = 2006, 2132) | 1.4 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 84 (n = 1189, 1215) | 9.0 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 12 (n = 2006, 2132) | 5.8 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 24 (n = 1895, 2017) | 6.2 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 36 (n = 1457, 1567) | 6.7 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit | Month 60 (n = 1424, 1518) | 7.9 percent change |
Secondary
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.
Time frame: Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
Population: Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 24 (n = 1924, 2041) | 8.4 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 60 (n = 1464, 1551) | 13.8 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 36 (n = 1487, 1589) | 10.1 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 84 (n = 1216, 1251) | 17.3 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 12 (n = 2030, 2148) | 5.9 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 84 (n = 1216, 1251) | 21.7 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 12 (n = 2030, 2148) | 11.9 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 24 (n = 1924, 2041) | 13.7 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 36 (n = 1487, 1589) | 15.2 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit | Month 60 (n = 1464, 1551) | 18.4 percent change |
Secondary
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.
Time frame: Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Population: Participants who received at least 1 dose of denosumab and enrolled in the bone turnover marker substudy at screening or Month 24 in Study 20060289. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 6 (n = 32, 57) | -74 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 48 (n = 61, 73) | -67 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 24 (n = 28, 51) | -67 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 60 (n = 61, 71) | -62 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 12 (n = 26, 56) | -74 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 72 (n = 56, 67) | -62 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 36 (n = 70, 83) | -59 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 84 (n =49, 53) | -68 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Day 10 (n = 30, 51) | 9 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 84 (n =49, 53) | -57 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Day 10 (n = 30, 51) | -59 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 6 (n = 32, 57) | -75 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 12 (n = 26, 56) | -63 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 24 (n = 28, 51) | -56 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 36 (n = 70, 83) | -60 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 48 (n = 61, 73) | -63 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 60 (n = 61, 71) | -55 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in P1NP by Visit | Month 72 (n = 56, 67) | -55 percent change |
Secondary
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.
Time frame: Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
Population: Participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. n indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 60 (n = 1424, 1518) | 4.9 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 24 (n = 1895, 2017) | 2.9 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 84 (n = 1189, 1215) | 6.1 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 36 (n = 1457, 1567) | 3.6 percent change |
| Placebo / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 12 (n = 2006, 2132) | 1.7 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 84 (n = 1189, 1215) | 9.2 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 60 (n = 1424, 1518) | 8.4 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 12 (n = 2006, 2132) | 6.4 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 24 (n = 1895, 2017) | 7.1 percent change |
| Denosumab / Denosumab | Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit | Month 36 (n = 1457, 1567) | 7.5 percent change |
Secondary
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.
Time frame: Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
Population: Participants who participated in the Study 20030216 PK substudy, for whom dosing information was not missing and for whom sampling was within 14 days of specified sampling times.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo / Denosumab | Serum Denosumab Concentration | Day 10 (n = 92, 106) | 5890 ng/mL | Standard Deviation 2010 |
| Placebo / Denosumab | Serum Denosumab Concentration | Month 4 (n = 87, 104) | 429 ng/mL | Standard Deviation 378 |
| Placebo / Denosumab | Serum Denosumab Concentration | Month 3 (n = 81, 92) | 1000 ng/mL | Standard Deviation 560 |
| Placebo / Denosumab | Serum Denosumab Concentration | Month 6 (n = 87, 103) | 20.8 ng/mL | Standard Deviation 61.7 |
| Placebo / Denosumab | Serum Denosumab Concentration | Baseline (n = 97, 113) | 0 ng/mL | Standard Deviation 0 |
| Denosumab / Denosumab | Serum Denosumab Concentration | Month 6 (n = 87, 103) | 66.0 ng/mL | Standard Deviation 147.2 |
| Denosumab / Denosumab | Serum Denosumab Concentration | Baseline (n = 97, 113) | 113 ng/mL | Standard Deviation 107 |
| Denosumab / Denosumab | Serum Denosumab Concentration | Day 10 (n = 92, 106) | 6010 ng/mL | Standard Deviation 2530 |
| Denosumab / Denosumab | Serum Denosumab Concentration | Month 3 (n = 81, 92) | 1190 ng/mL | Standard Deviation 690 |
| Denosumab / Denosumab | Serum Denosumab Concentration | Month 4 (n = 87, 104) | 554 ng/mL | Standard Deviation 480 |