Trial Outcomes & Findings for A Transiliac Crest Bone Histology and Histomorphometry Study in Postmenopausal Women With Low Bone Mass or Osteoporosis Previously Treated With Denosumab (NCT NCT00887965)

NCT ID: NCT00887965

Last Updated: 2013-11-15

Results Overview

The number of participants with normal/abnormal bone histology as assessed by bone biopsy samples at the central histomorphometric facility. Normal bone histology is characterized by: - normal lamellar bone, - normal mineralization or - osteoid (the organic matrix of bone; young bone that has not undergone calcification). Biopsies with abnormal bone histology are characterized by: - osteomalacia, - marrow fibrosis, - clinically significant marrow abnormality or - woven bone.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 15 participants
• Primary outcome timeframe: 25-34 days post-Day 1
• Results posted on: 2013-11-15

Participant Flow

First subject enrolled on 02-JUN-09. Last subject enrolled on 28-APR-2010.

Participant milestones

Measure	Previous Denosumab Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Overall Study STARTED	15
Overall Study COMPLETED	15
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Transiliac Crest Bone Histology and Histomorphometry Study in Postmenopausal Women With Low Bone Mass or Osteoporosis Previously Treated With Denosumab

Baseline characteristics by cohort

Measure	Previous Denosumab n=15 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Age Continuous	62.1 Years STANDARD_DEVIATION 5.9 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Ethnic group: White or Caucasian	15 Participants n=5 Participants

PRIMARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients who had at least one evaluable biopsy

The number of participants with normal/abnormal bone histology as assessed by bone biopsy samples at the central histomorphometric facility. Normal bone histology is characterized by: - normal lamellar bone, - normal mineralization or - osteoid (the organic matrix of bone; young bone that has not undergone calcification). Biopsies with abnormal bone histology are characterized by: - osteomalacia, - marrow fibrosis, - clinically significant marrow abnormality or - woven bone.

Outcome measures

Measure	Previous Denosumab n=15 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Number of Participants With Normal/Abnormal Bone Histology Normal lamellar bone	15 Participants
Number of Participants With Normal/Abnormal Bone Histology Normal mineralization	15 Participants
Number of Participants With Normal/Abnormal Bone Histology Osteoid	15 Participants
Number of Participants With Normal/Abnormal Bone Histology Osteomalacia	0 Participants
Number of Participants With Normal/Abnormal Bone Histology Marrow fibrosis	0 Participants
Number of Participants With Normal/Abnormal Bone Histology Clinically significant marrow abnormality	0 Participants
Number of Participants With Normal/Abnormal Bone Histology Woven bone	0 Participants

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry

Cancellous (trabecular) bone volume (Tb.V) is the relative volume of total cancellous bone measured (TV), expressed as percentage, that is occupied by trabeculae. Cancellous bone volume was measured using Fluorochrome labeling with tetracyclene and tartrate-resistant acid phosphatase stain (TRAP) staining techniques.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Cancellous Bone Volume Fluorochrome labeling	13.765 percentage of total volume Interval 10.19 to 18.08
Bone Histomorphometry: Cancellous Bone Volume TRAP staining	17.320 percentage of total volume Interval 12.54 to 23.23

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Trabecular number (Tb.N) is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Tb.N is a measure of trabecular connectivity and decreases with bone loss.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Trabecular Number	1.050 mm^-1 Interval 1.0 to 1.16

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Trabecular separation (Tb.Sp) is the mean distance in mm between trabeculae (measured by integrated computer graphics). Tb.Sp increases with trabecular bone loss.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Trabecular Separation	807.270 μm Interval 705.69 to 896.11

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Mean trabecular thickness (Tb.Th) is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Tb.Th is reduced by aging and osteoporosis.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Trabecular Thickness	131.465 μm Interval 117.09 to 159.03

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Cortical width correlates with dual photon absorptiometric (DPX) measurements of bone density.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Cortical Width	747.45 μm Interval 524.5 to 845.4

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Surface density is calculated by total bone (trabecular) surfaces / total tissue volume.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Surface Density	2.110 mm^2 /mm^3 Interval 2.0 to 2.32

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Osteoblast - Osteoid Interface	30.165 percentage of osteoid surface Interval 8.99 to 41.21

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Osteoid surface is expressed as a percentage total bone surface.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Osteoid Surface	3.280 percentage of bone surface Interval 1.2 to 8.37

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Osteoid thickness (width; O.Th) is the mean thickness of osteoid seams on cancellous surfaces. O.Th is normally <12.5 µm. Increased O.Th suggests abnormal mineralization (osteomalacia).

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Osteoid Width	7.675 μm Interval 6.68 to 11.88

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for 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.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Wall Thickness	40.30 μm Interval 38.1 to 53.3

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Eroded surface is expressed as a percentage of total bone surface.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Eroded Surface/Bone Surface	0.525 percentage of bone surface Interval 0.3 to 1.11

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Osteoclast number expressed per mm of bone. Osteoclast number was measured using fluorochrome labeling with tetracyclene and tartrate-resistant acid phosphatase stain (TRAP) staining techniques.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Osteoclast Number - Length Based Fluorochrome labeling	0.150 1/mm Interval 0.047 to 0.214
Bone Histomorphometry: Osteoclast Number - Length Based TRAP staining	0.122 1/mm Interval 0.07 to 0.25

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Osteoclast number expressed per bone surface area. Osteoclast number was measured using fluorochrome labeling with tetracyclene and tartrate-resistant acid phosphatase stain (TRAP) staining techniques.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Osteoclast Number - Surface Based Fluorochrome labeling	15.0 1/100 mm Interval 14.7 to 21.4
Bone Histomorphometry: Osteoclast Number - Surface Based TRAP staining	12.2 1/100 mm Interval 7.0 to 25.0

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Single-label surface is expressed as a percentage of total bone surface. The presence of a single label indicates that mineralization was occurring during only one labeling period.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Single-label Surface	2.655 percentage of bone surface Interval 1.52 to 3.55

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Double-label surface is expressed as a percentage of total bone surface. The presence of double labels indicates that normal bone mineralization was actively occurring over the labeling interval.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Double-label Surface	2.895 percentage of bone surface Interval 1.61 to 4.23

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Total Mineralizing Surface	4.470 percentage of bone surface Interval 3.13 to 5.88

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

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.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Mineral Apposition Rate	0.740 μm/day Interval 0.63 to 0.89

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

The mineral apposition rate (MAR) is the avarage 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).

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Adjusted Mineral Apposition Rate	0.750 μm/day Interval 0.41 to 1.34

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Bone formation rate - surface based (BFR/BS) is the calculated rate at which cancellous bone surface is being replaced annually. BFR/BS is derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface /total bone surface).

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Bone Formation Rate - Surface Based	11.930 μm^3 /μm^2 /year Interval 10.56 to 14.86

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Bone formation rate - volume based (BFR/BV) is the calculated rate at which cancellous bone volume is being replaced annually. BFR/BV is derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone volume).

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Bone Formation Rate - Volume Based	18.780 percent of bone volume per year Interval 12.05 to 27.34

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

The formation period is the duration of an interval when a place on the bone surface is actively forming bone. The formation period is calculated as the wall width (thickness of new bone made in one cycle) divided by the mineral apposition rate.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Formation Period	60.7 days Interval 32.4 to 88.4

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

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 (Ac.f). Activation frequency is calculated as the bone formation rate / wall width.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Activation Frequency	0.261 /year Interval 0.198 to 0.36

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

Osteoid volume is expressed as a percentage of total bone volume.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Osteoid Volume	0.515 percentage of total volume Interval 0.12 to 1.36

SECONDARY outcome

Timeframe: 25-34 days post-Day 1

Population: All enrolled patients with at least one biopsy evaluable for histomorphometry.

The mineralization lag time is the time interval between osteoid secretion and its subsequent mineralization, in days.

Outcome measures

Measure	Previous Denosumab n=14 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Bone Histomorphometry: Mineralization Lag Time	11.9 days Interval 7.6 to 19.9

SECONDARY outcome

Timeframe: Day 3 or Day 20

Population: All enrolled patients with at least one evaluable biopsy

C-Telopeptide is a biochemical marker for bone turnover. Blood samples were drawn for assessment of CTX-1 levels on either Day 3 or Day 20, within 24 hours of the last dose of the respective tetracycline cycle.

Outcome measures

Measure	Previous Denosumab n=15 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
C-Telopeptide (CTX-1)	0.646 ng/mL Interval 0.494 to 0.789

SECONDARY outcome

Timeframe: Day 3 or Day 20

Population: All enrolled patients with at least one evaluable biopsy

Procollagen Type 1 N-terminal Peptide is a biochemical marker of bone turnover. Blood samples were drawn for assessment of P1NP levels on either Day 3 or Day 20, within 24 hours of the last dose of the respective tetracycline cycle.

Outcome measures

Measure	Previous Denosumab n=15 Participants Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Procollagen Type 1 N-terminal Peptide (P1NP)	50.70 μg/L Interval 40.8 to 58.9

Adverse Events

Previous Denosumab

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Previous Denosumab n=15 participants at risk Participants who had previously received Denosumab 60 mg every 6 months and had transiliac bone biopsy.
Gastrointestinal disorders Dyspepsia	6.7% 1/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Nausea	13.3% 2/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Vomiting	6.7% 1/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Injury, poisoning and procedural complications Post procedural haematoma	40.0% 6/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Injury, poisoning and procedural complications Procedural pain	80.0% 12/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Myalgia	6.7% 1/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Nervous system disorders Hypoaesthesia	6.7% 1/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Vascular disorders Hot flush	13.3% 2/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Vascular disorders Hypertension	6.7% 1/15 • up to 50 days The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

• Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, the investigator agrees not to publish any results before the first multi-center publication.
• Publication restrictions are in place

Restriction type: OTHER