A Phase 3 interventional study of Denosumab in Osteopenia and Osteoporosis, sponsored by Amgen. Completed. Open to female participants aged 60 Years to 94 Years. Per ClinicalTrials.gov, last updated 2022-11-07.
Sponsored by Amgen · Phase 3, Interventional, and Treatment
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.
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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
Exclusion Criteria
Participants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years.
Biological: Denosumab
Administered by subcutaneous injection once every 6 months.
Also known as: AMG 162, Prolia
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
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
Number of Participants With Antibodies to Denosumab
Time frame: Every 12 months through Month 84
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
Time frame: Baseline (of extension study) and day 10
Serum Denosumab Concentration
Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 0.8 ng/mL. Values of 0 in the table below indicate data below the lower limit of quantification.
Time frame: Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
Bone Histomorphometry: Cancellous Bone Volume
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by quantitative histomorphometry.
Time frame: Month 24 and month 84
Bone Histomorphometry: Trabecular Number
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular number is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Trabecular number is a measure of trabecular connectivity and decreases with bone loss.
Time frame: Month 24 and month 84
Bone Histomorphometry: Trabecular Separation
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular separation is the mean distance between trabeculae (measured by integrated computer graphics). Trabecular separation increases with trabecular bone loss.
Time frame: Month 24 and month 84
Bone Histomorphometry: Trabecular Thickness
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Mean trabecular thickness is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Trabecular thickness is reduced by aging and osteoporosis.
Time frame: Month 24 and month 84
Bone Histomorphometry: Cortical Width
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices.
Time frame: Month 24 and month 84
Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by tartrate-resistant acid phosphatase (TRAP) staining histomorphometry.
Time frame: Month 24 and month 84
Bone Histomorphometry: Surface Density
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoblast - Osteoid Interface
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface \* 100.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoid Surface
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoid Thickness
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid thickness (width) is the mean thickness of osteoid seams on cancellous surfaces. Osteoid thickness is normally \<12.5 µm. Increased osteoid thickness suggests abnormal mineralization (osteomalacia).
Time frame: Month 24 and month 84
Bone Histomorphometry: Wall Thickness
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Wall thickness is the average thickness of trabecular bone structural units (BSU) and is used to assess the overall balance between resorption and formation.
Time frame: Month 24 and month 84
Bone Histomorphometry: Eroded Surface/Bone Surface
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Eroded surface/bone surface is the percentage of bone surface occupied by eroded (resorption) cavities (Howships lacunae), with or without osteoclasts.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number - Length Based
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per mm of bone.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number - Surface Based
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per 100 mm of bone surface area.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per mm of bone.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per 100 mm of bone surface. Da
Time frame: Month 24 and month 84
Bone Histomorphometry: Single-label Surface
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. A single label is deposited if formation either started or ended during the interval between the uses of the two courses of tetracycline administration. Single-label surface is expressed as a percentage of total bone surface.
Time frame: Month 24 and month 84
Bone Histomorphometry: Double-label Surface
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The presence of double labels indicates that normal bone mineralization was actively occurring over the entire labeling interval. Double-label surface is expressed as a percentage of total bone surface.
Time frame: Month 24 and month 84
Bone Histomorphometry: Mineralizing Surface
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface.
Time frame: Month 24 and month 84
Bone Histomorphometry: Mineral Apposition Rate
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. MAR is calculated as the average distance between visible labels, divided by the labeling interval.
Time frame: Month 24 and month 84
Bone Histomorphometry: Adjusted Apposition Rate
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the average rate at which new bone mineral is being added on any actively forming surface. Adjusted MAR is calculated as: (average distance between visible labels / labeling interval) \* (total mineralizing surface/total bone surface).
Time frame: Month 24 and month 84
Bone Histomorphometry: Bone Formation Rate - Surface Based
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - surface based is the calculated rate at which cancellous bone surface is being replaced annually, derived from the Mineral Appositional Rate \* 365 \* (relative mineralizing surface / total bone surface).
Time frame: Month 24 and month 84
Bone Histomorphometry: Bone Formation Rate - Volume Based
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - volume based is the calculated rate at which cancellous bone volume is being replaced annually, derived from the Mineral Appositional Rate \* 365 \* (relative mineralizing surface / total bone volume).
Time frame: Month 24 and month 84
Bone Histomorphometry: Formation Period
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Formation period (FP) is the mean time required to rebuild a new bone structural unit or osteon from the cement line back to the bone surface at a single location, and is given by wall width / adjusted apposition rate.
Time frame: Month 24 and month 84
Bone Histomorphometry: Activation Frequency
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The average time that it takes for a new remodeling cycle to begin on any point on a cancellous surface is called the activation frequency. Activation frequency is calculated as the bone formation rate / wall width.
Time frame: Month 24 and month 84
Bone Histomorphometry: Osteoid Volume
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid volume is the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).
Time frame: Month 24 and month 84
Bone Histomorphometry: Mineralization Lag Time
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Mineralization lag time is the average time interval between osteoid formation and its subsequent mineralization and is calculated by dividing the osteoid width by the apposition rate.
Time frame: Month 24 and month 84
Bone Histology at Month 24
Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.
Time frame: Month 24
Bone Histology at Month 84
Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone.
Time frame: Month 84
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.
| Milestone | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Started | 2207 | 2343 |
| Received treatment | 2206 | 2343 |
| Completed | 1283 | 1343 |
| Not completed | 924 | 1000 |
| Withdrew: Withdrawal by subject | 399 | 427 |
| Withdrew: Other | 181 | 198 |
| Withdrew: Adverse event | 122 | 155 |
| Withdrew: Death | 101 | 110 |
| Withdrew: Lost to follow-up | 73 | 61 |
| Withdrew: Non-compliance | 20 | 13 |
| Withdrew: Physician decision | 14 | 13 |
| Withdrew: Requirement for alternative therapy | 4 | 14 |
| Withdrew: Protocol deviation | 6 | 5 |
| Withdrew: Ineligibility determined | 3 | 4 |
| Withdrew: Disease progression | 1 | 0 |
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.
| participants | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Any adverse event (AE) | 2070 | 2173 |
| Serious adverse event | 945 | 1014 |
| Fatal adverse event | 101 | 108 |
| AE leading to study discontinuation | 145 | 173 |
| AE leading to discontinuation of denosumab | 184 | 216 |
| Treatment-related adverse events (TRAE) | 185 | 188 |
| Serious treatment-related adverse events | 26 | 28 |
| Fatal treatment-related adverse events | 1 | 0 |
| TRAE leading to study discontinuation | 16 | 9 |
| TRAE leading to discontinuation of denosumab | 30 | 25 |
| Positively adjudicated osteonecrosis of the jaw | 6 | 7 |
| Positively adjudicated atypical femoral fracture | 1 | 1 |
| Hypocalcaemia | 10 | 6 |
| AEs potentially related to hypersensitivity | 260 | 280 |
| Serious infections | 161 | 185 |
| Serious bacterial cellulitis | 7 | 12 |
| Malignancy | 227 | 237 |
| Cardiac disorders | 449 | 492 |
| Vascular disorders | 693 | 732 |
| Fracture healing complications | 0 | 1 |
| Eczema | 99 | 115 |
| Acute pancreatitis | 4 | 8 |
| Musculoskeletal pain | 1125 | 1206 |
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.
| participants | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Low sodium - Grade 3 | 28 | 25 |
| Low sodium - Grade 4 | 1 | 0 |
| High potassium - Grade 3 | 9 | 11 |
| High potassium - Grade 4 | 0 | 3 |
| Low potassium - Grade 3 | 7 | 7 |
| Low magnesium - Grade 3 | 1 | 1 |
| Low magnesium - Grade 4 | 0 | 1 |
| High calcium - Grade 3 | 2 | 3 |
| High calcium - Grade 4 | 0 | 2 |
| High corrected calcium - Grade 3 | 2 | 3 |
| High corrected calcium - Grade 4 | 0 | 2 |
| Low phosphorus - Grade 3 | 3 | 1 |
| High Creatinine - Grade 3 | 0 | 1 |
| High aspartate amino transferase (AST) - Grade 3 | 5 | 11 |
| High aspartate amino transferase (AST) - Grade 4 | 1 | 0 |
| High alanine amino transferase (ALT) - Grade 3 | 8 | 10 |
| High alanine amino transferase (ALT) - Grade 4 | 1 | 0 |
| High total bilirubin - Grade 3 | 2 | 3 |
| Low albumin - Grade 3 | 0 | 1 |
| High glucose - Grade 3 | 35 | 37 |
| High glucose - Grade 4 | 0 | 1 |
| Low glucose - Grade 3 | 4 | 1 |
| Low glucose - Grade 4 | 1 | 1 |
| Low hemoglobin - Grade 3 | 6 | 4 |
| Low platelets - Grade 3 | 3 | 7 |
| Low platelets - Grade 4 | 2 | 4 |
| Low white blood cells - Grade 3 | 5 | 7 |
| Low white blood cells - Grade 4 | 0 | 1 |
| Low lymphocytes - Grade 3 | 17 | 16 |
| Low lymphocytes - Grade 4 | 2 | 1 |
| participants | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Number of Participants With Antibodies to Denosumab | 1 | 0 |
Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
| percent change | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 2040, 2168) | 5.2 (5.0 to 5.3) | 2.0 (1.8 to 2.2) |
| Month 24 (n = 1935, 2061) | 7.7 (7.5 to 7.9) | 3.5 (3.4 to 3.7) |
| Month 36 (n = 1497, 1607) | 9.4 (9.1 to 9.6) | 4.9 (4.7 to 5.1) |
| Month 60 (n = 1472, 1567) | 13.0 (12.7 to 13.3) | 7.9 (7.6 to 8.2) |
| Month 84 (n = 1223, 1264) | 16.5 (16.1 to 16.9) | 10.8 (10.4 to 11.2) |
Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
| percent change | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 2029, 2160) | 3.0 (2.8 to 3.1) | 0.8 (0.7 to 0.9) |
| Month 24 (n = 1918, 2045) | 4.1 (4.0 to 4.2) | 1.4 (1.3 to 1.5) |
| Month 36 (n = 1475, 1591) | 4.9 (4.7 to 5.0) | 1.8 (1.7 to 2.0) |
| Month 60 (n = 1439, 1538) | 6.2 (6.0 to 6.4) | 2.6 (2.4 to 2.8) |
| Month 84 (n = 1200, 1232) | 7.4 (7.1 to 7.6) | 3.4 (3.2 to 3.7) |
Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
| percent change | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 2029, 2160) | 2.1 (1.9 to 2.3) | 0.8 (0.7 to 1.0) |
| Month 24 (n = 1918, 2045) | 3.2 (3.1 to 3.4) | 1.2 (1.0 to 1.4) |
| Month 36 (n = 1475, 1591) | 4.0 (3.8 to 4.3) | 1.7 (1.5 to 1.9) |
| Month 60 (n = 1439, 1538) | 5.7 (5.4 to 5.9) | 2.8 (2.6 to 3.1) |
| Month 84 (n = 1200, 1232) | 7.1 (6.8 to 7.4) | 3.8 (3.5 to 4.2) |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 114, 134) | 0.3 (-0.2 to 0.9) | 0.6 (0.1 to 1.2) |
| Month 24 (n = 108, 127) | 0.2 (-0.4 to 0.9) | 0.2 (-0.4 to 0.8) |
| Month 36 (n = 73, 93) | 1.3 (0.5 to 2.0) | 0.6 (-0.1 to 1.3) |
| Month 60 (n = 59, 84) | 1.8 (0.9 to 2.7) | 1.4 (0.6 to 2.2) |
| Month 84 (n = 39, 56) | 2.2 (0.9 to 3.6) | 1.0 (-0.1 to 2.2) |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 2030, 2148) | 5.9 (5.6 to 6.1) | 11.9 (11.7 to 12.2) |
| Month 24 (n = 1924, 2041) | 8.4 (8.1 to 8.7) | 13.7 (13.4 to 13.9) |
| Month 36 (n = 1487, 1589) | 10.1 (9.8 to 10.4) | 15.2 (14.9 to 15.5) |
| Month 60 (n = 1464, 1551) | 13.8 (13.4 to 14.1) | 18.4 (18.1 to 18.8) |
| Month 84 (n = 1216, 1251) | 17.3 (16.8 to 17.8) | 21.7 (21.2 to 22.2) |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 2006, 2132) | 1.7 (1.6 to 1.9) | 6.4 (6.3 to 6.6) |
| Month 24 (n = 1895, 2017) | 2.9 (2.7 to 3.0) | 7.1 (6.9 to 7.2) |
| Month 36 (n = 1457, 1567) | 3.6 (3.4 to 3.8) | 7.5 (7.3 to 7.7) |
| Month 60 (n = 1424, 1518) | 4.9 (4.7 to 5.2) | 8.4 (8.1 to 8.6) |
| Month 84 (n = 1189, 1215) | 6.1 (5.8 to 6.4) | 9.2 (8.9 to 9.5) |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 2006, 2132) | 1.4 (1.2 to 1.7) | 5.8 (5.6 to 6.0) |
| Month 24 (n = 1895, 2017) | 2.6 (2.3 to 2.8) | 6.2 (6.0 to 6.5) |
| Month 36 (n = 1457, 1567) | 3.4 (3.1 to 3.6) | 6.7 (6.5 to 7.0) |
| Month 60 (n = 1424, 1518) | 5.0 (4.7 to 5.3) | 7.9 (7.6 to 8.2) |
| Month 84 (n = 1189, 1215) | 6.4 (6.0 to 6.8) | 9.0 (8.6 to 9.4) |
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.
| percent change | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 12 (n = 113, 133) | -1.0 (-1.7 to -0.3) | 2.6 (1.9 to 3.2) |
| Month 24 (n = 107, 127) | -1.2 (-1.9 to -0.4) | 2.1 (1.4 to 2.8) |
| Month 36 (n = 73, 92) | -0.2 (-1.1 to 0.7) | 2.4 (1.6 to 3.2) |
| Month 60 (n = 59, 83) | 0.3 (-0.7 to 1.3) | 3.3 (2.4 to 4.2) |
| Month 84 (n = 39, 56) | 0.6 (-0.8 to 2.1) | 2.8 (1.6 to 4.1) |
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.
| participants | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Number of Participants With New Vertebral Fractures | 145 | 149 |
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.
| participants | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Number of Participants With Non-Vertebral Fractures | 219 | 172 |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Day 10 (n = 26, 47) | -90 (-93 to -85) | -72 (-86 to -47) |
| Month 6 (n = 30, 56) | -85 (-91 to -73) | -26 (-63 to 1) |
| Month 12 (n = 27, 56) | -75 (-90 to -54) | -13 (-37 to 24) |
| Month 24 (n = 27, 47) | -67 (-84 to -29) | 10 (-27 to 55) |
| Month 36 (n = 68, 81) | -59 (-84 to -28) | 2 (-32 to 68) |
| Month 48 (n = 62, 75) | -58 (-84 to -12) | 0 (-46 to 56) |
| Month 60 (n = 59, 70) | -65 (-90 to -19) | 0 (-47 to 83) |
| Month 72 (n = 56, 62) | -60 (-85 to -16) | -1 (-47 to 76) |
| Month 84 (n = 41, 41) | -64 (-86 to -28) | -6 (-26 to 68) |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Day 10 (n = 30, 51) | 6 (-5 to 30) | 14 (-1 to 25) |
| Month 6 (n = 30, 53) | -71 (-78 to -62) | -23 (-50 to -2) |
| Month 12 (n = 26, 56) | -67 (-76 to -57) | 7 (-15 to 30) |
| Month 24 (n = 27, 47) | -63 (-77 to -41) | 11 (-17 to 42) |
| Month 36 (n = 69, 83) | -57 (-67 to -29) | 29 (-6 to 91) |
| Month 48 (n = 61, 73) | -60 (-70 to -41) | 8 (-21 to 49) |
| Month 60 (n = 61, 71) | -54 (-72 to -35) | 30 (-6 to 67) |
| Month 72 (n = 55, 64) | -50 (-60 to -36) | 44 (3 to 103) |
| Month 84 (n = 48, 50) | -59 (-73 to -40) | 32 (-4 to 75) |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Day 10 (n = 26, 56) | -90 (-91 to -78) | -91 (-93 to -86) |
| Month 6 (n = 32, 72) | -83 (-90 to -72) | -77 (-87 to -49) |
| Month 12 (n = 27, 65) | -77 (-91 to -45) | -63 (-87 to -11) |
| Month 24 (n = 28, 60) | -65 (-80 to -24) | -53 (-82 to 0) |
| Month 36 (n = 289, 313) | -71 (-88 to -40) | -52 (-86 to -4) |
| Month 48 (n = 274, 290) | -70 (-88 to -36) | -61 (-85 to -24) |
| Month 60 (n = 268, 276) | -67 (-88 to -25) | -53 (-86 to -18) |
| Month 72 (n = 243, 248) | -69 (-88 to -32) | -59 (-86 to -21) |
| Month 84 (n = 217, 216) | -63 (-88 to -19) | -53 (-84 to -12) |
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 | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Day 10 (n = 30, 51) | 9 (-14 to 34) | -59 (-74 to -22) |
| Month 6 (n = 32, 57) | -74 (-80 to -67) | -75 (-80 to -55) |
| Month 12 (n = 26, 56) | -74 (-79 to -51) | -63 (-76 to -36) |
| Month 24 (n = 28, 51) | -67 (-75 to -51) | -56 (-72 to -30) |
| Month 36 (n = 70, 83) | -59 (-75 to -37) | -60 (-71 to -40) |
| Month 48 (n = 61, 73) | -67 (-75 to -46) | -63 (-77 to -42) |
| Month 60 (n = 61, 71) | -62 (-75 to -42) | -55 (-74 to -30) |
| Month 72 (n = 56, 67) | -62 (-71 to -35) | -55 (-70 to -27) |
| Month 84 (n =49, 53) | -68 (-78 to -56) | -57 (-74 to -38) |
| percent change | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10 | -3.1 (-6.1 to 0.0) | -2.0 (-5.1 to 1.1) |
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.
| ng/mL | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Baseline (n = 97, 113) | 0 ± 0 | 113 ± 107 |
| Day 10 (n = 92, 106) | 5890 ± 2010 | 6010 ± 2530 |
| Month 3 (n = 81, 92) | 1000 ± 560 | 1190 ± 690 |
| Month 4 (n = 87, 104) | 429 ± 378 | 554 ± 480 |
| Month 6 (n = 87, 103) | 20.8 ± 61.7 | 66.0 ± 147.2 |
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.
| percentage of total bone tissue volume | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 15.253 ± 6.065 | 14.640 ± 6.979 |
| Month 84 (n = 0, 19) | NA ± NA | 16.358 ± 4.438 |
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.
| 1/mm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 1.005 ± 0.242 | 0.904 ± 0.243 |
| Month 24 (n = 0, 19) | NA ± NA | 1.235 ± 0.254 |
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.
| μm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 919.693 ± 358.238 | 1033.416 ± 352.259 |
| Month 84 (n = 0, 19) | NA ± NA | 708.669 ± 171.782 |
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.
| μm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 153.878 ± 51.859 | 156.335 ± 48.567 |
| Month 84 (n = 0, 19) | NA ± NA | 132.965 ± 28.064 |
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices.
| μm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 28) | 622.22 ± 246.70 | 707.69 ± 237.97 |
| Month 84 (n = 0, 21) | NA ± NA | 786.19 ± 279.81 |
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.
| percentage of total bone tissue volume | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 16.678 ± 7.270 | 15.606 ± 6.986 |
| Month 84 (n = 0, 19) | NA ± NA | 17.631 ± 4.387 |
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume.
| mm²/mm³ | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 2.009 ± 0.486 | 1.807 ± 0.486 |
| Month 84 (n = 0, 19) | NA ± NA | 2.472 ± 0.506 |
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface \* 100.
| percentage of osteoid surface | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 22.124 ± 34.879 | 17.813 ± 28.381 |
| Month 84 (n = 0, 19) | NA ± NA | 5.951 ± 15.223 |
Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid.
| percentage of total bone surface | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 0.915 ± 1.382 | 0.982 ± 2.489 |
| Month 84 (n = 0, 19) | NA ± NA | 0.421 ± 1.068 |
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).
| μm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 5.139 ± 3.261 | 4.548 ± 4.973 |
| Month 84 (n = 0, 19) | NA ± NA | 4.108 ± 3.476 |
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.
| μm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 43.11 ± 6.08 | 49.74 ± 10.51 |
| Month 84 (n = 0, 19) | NA ± NA | 39.59 ± 7.49 |
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.
| percentage of bone surface | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 0.414 ± 0.701 | 0.328 ± 0.613 |
| Month 84 (n = 0, 19) | NA ± NA | 0.511 ± 0.579 |
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.
| 1/mm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 0.086 ± 0.119 | 0.107 ± 0.198 |
| Month 84 (n = 0, 19) | NA ± NA | 0.074 ± 0.101 |
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.
| 1/100 mm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 8.6 ± 11.9 | 10.7 ± 19.8 |
| Month 84 (n = 0, 19) | NA ± NA | 7.4 ± 10.1 |
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.
| 1/mm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 0.096 ± 0.134 | 0.110 ± 0.185 |
| Month 84 (n = 0, 19) | NA ± NA | 0.077 ± 0.107 |
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
| 1/100 mm | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 9.6 ± 13.4 | 11.0 ± 18.5 |
| Month 84 (n = 0, 19) | NA ± NA | 7.7 ± 10.7 |
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.
| percentage of bone surface | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 0.304 ± 0.302 | 0.643 ± 0.661 |
| Month 84 (n = 0, 10) | NA ± NA | 0.611 ± 0.726 |
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.
| percentage of bone surface | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 0.258 ± 0.207 | 0.356 ± 0.295 |
| Month 84 (n = 0, 10) | NA ± NA | 0.106 ± 0.237 |
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.
| percentage of bone surface | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 0.406 ± 0.323 | 0.681 ± 0.453 |
| Month 84 (n = 0, 10) | NA ± NA | 0.412 ± 0.458 |
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.
| μm/day | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 0.616 ± 0.219 | 0.722 ± 0.573 |
| Month 84 (n = 0, 10) | NA ± NA | 0.394 ± 0.233 |
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).
| μm/day | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 9) | 0.394 ± 0.471 | 0.517 ± 0.537 |
| Month 84 (n = 0, 10) | NA ± NA | 0.818 ± 1.207 |
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).
| μm³/μm²/year | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 0.898 ± 0.706 | 2.153 ± 2.468 |
| Month 84 (n = 0, 10) | NA ± NA | 0.691 ± 0.868 |
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).
| percent of bone volume per year | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 1.454 ± 1.265 | 3.162 ± 3.773 |
| Month 84 (n = 0, 10) | NA ± NA | 1.071 ± 1.308 |
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.
| days | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 593.5 ± 996.8 | 287.3 ± 391.5 |
| Month 84 (n = 0, 10) | NA ± NA | 229.7 ± 512.0 |
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.
| /year | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 0.022 ± 0.019 | 0.045 ± 0.049 |
| Month 84 (n = 0, 10) | NA ± NA | 0.014 ± 0.024 |
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).
| percentage of total bone tissue | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 13, 25) | 0.108 ± 0.193 | 0.146 ± 0.382 |
| Month 84 (n = 0, 19) | NA ± NA | 0.048 ± 0.133 |
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.
| days | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Month 24 (n = 5, 10) | 84.9 ± 136.8 | 54.3 ± 76.1 |
| Month 84 (n = 0, 10) | NA ± NA | 52.3 ± 114.5 |
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.
| biopsies | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Normal lamellar bone | 13 | 28 |
| Normal mineralization | 13 | 28 |
| Osteoid | 13 | 23 |
| Osteomalacia | 0 | 0 |
| Marrow fibrosis | 0 | 0 |
| Woven bone | 0 | 0 |
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.
| biopsies | Placebo / Denosumab | Denosumab / Denosumab |
|---|---|---|
| Normal lamellar bone | — | 22 |
| Normal mineralization | — | 22 |
| Osteoid | — | 18 |
| Osteomalacia | — | 0 |
| Marrow fibrosis | — | 0 |
| Woven bone | — | 0 |
Collected over 84 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo/ Denosumab 60 mg Q6M | — | 945/2,206 (42.8%) | 1,809/2,206 (82%) |
| Denosumab/ Denosumab 60 mg Q6M | — | 1,014/2,343 (43.3%) | 1,920/2,343 (81.9%) |
| Event | Placebo/ Denosumab 60 mg Q6M | Denosumab/ Denosumab 60 mg Q6M |
|---|---|---|
| OsteoarthritisMusculoskeletal and connective tissue disorders | 79/2206 | 99/2343 |
| Atrial fibrillationCardiac disorders | 50/2206 | 40/2343 |
| PneumoniaInfections and infestations | 44/2206 | 48/2343 |
| CholelithiasisHepatobiliary disorders | 22/2206 | 30/2343 |
| Cerebrovascular accidentNervous system disorders | 22/2206 | 29/2343 |
| Radius fractureInjury, poisoning and procedural complications | 25/2206 | 22/2343 |
| Myocardial infarctionCardiac disorders | 21/2206 | 24/2343 |
| Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 21/2206 | 24/2343 |
| Transient ischaemic attackNervous system disorders | 21/2206 | 19/2343 |
| Spinal column stenosisMusculoskeletal and connective tissue disorders | 14/2206 | 22/2343 |
| Event | Placebo/ Denosumab 60 mg Q6M | Denosumab/ Denosumab 60 mg Q6M |
|---|---|---|
| ArthralgiaMusculoskeletal and connective tissue disorders | 527/2206 | 541/2343 |
| Back painMusculoskeletal and connective tissue disorders | 501/2206 | 493/2343 |
| HypertensionVascular disorders | 460/2206 | 498/2343 |
| NasopharyngitisInfections and infestations | 372/2206 | 385/2343 |
| OsteoarthritisMusculoskeletal and connective tissue disorders | 332/2206 | 355/2343 |
| CataractEye disorders | 319/2206 | 317/2343 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 264/2206 | 293/2343 |
| FallInjury, poisoning and procedural complications | 240/2206 | 268/2343 |
| Urinary tract infectionInfections and infestations | 242/2206 | 250/2343 |
| Musculoskeletal painMusculoskeletal and connective tissue disorders | 197/2206 | 231/2343 |
| Age, Continuous(years) | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| Mean | 74.8 ± 5.1 | 74.9 ± 5.0 | 74.8 ± 5.0 |
| Age, Customized(participants) | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| 60 - 64 years | 58 | 49 | 107 |
| 65 - 69 years | 326 | 320 | 646 |
| 70 - 74 years | 672 | 716 | 1388 |
| ≥ 75 years | 1151 | 1258 | 2409 |
| Sex: Female, Male(Participants) | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| Female | 2207 | 2343 | 4550 |
| Male | 0 | 0 | 0 |
| Race/Ethnicity, Customized(participants) | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| White | 2063 | 2169 | 4232 |
| Black | 16 | 19 | 35 |
| Hispanic or Latino | 121 | 145 | 266 |
| Asian | 2 | 3 | 5 |
| Japanese | 3 | 5 | 8 |
| Native Hawaiian or Other Pacific Islander | 1 | 0 | 1 |
| Other | 1 | 2 | 3 |
| Bone Mineral Density T-score(T-score) | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| Lumbar spine | -2.81 ± 0.75 | -2.14 ± 0.80 | -2.47 ± 0.84 |
| Total hip | -1.93 ± 0.80 | -1.50 ± 0.79 | -1.71 ± 0.83 |
| Femoral neck | -2.17 ± 0.72 | -1.83 ± 0.75 | -1.99 ± 0.75 |
| Bone Mineral Density T-score at Study 20030216 Baseline(T-score) | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| Lumbar spine | -2.84 ± 0.68 | -2.83 ± 0.67 | -2.83 ± 0.68 |
| Total hip | -1.85 ± 0.79 | -1.85 ± 0.79 | -1.85 ± 0.79 |
| Femoral neck | -2.11 ± 0.71 | -2.11 ± 0.71 | -2.11 ± 0.71 |
| Any Historical Fracture at Age ≥ 55 Years(participants) | Placebo / Denosumab | Denosumab / Denosumab | Total |
|---|---|---|---|
| Number | 1089 | 1133 | 2222 |
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