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

Osteoporosis Clinical Trial

Official title:

An Open Label, Single Arm, Extension Study to Evaluate the Long Term Safety and Sustained Efficacy of Denosumab (AMG162) in the Treatment of Postmenopausal Osteoporosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00523341
• Other study ID #: 20060289
• Status: Completed
• Phase: Phase 3
• Start date: August 7, 2007
• Est. completion date: July 19, 2015

Study information

• Verified date: November 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective was to describe the safety and tolerability of up to 10 years or 7 years denosumab administration as measured by adverse event monitoring, immunogenicity and safety laboratory parameters in participants who previously received denosumab or placebo, respectively.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4550
• Est. completion date: July 19, 2015
• Est. primary completion date: July 19, 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 60 Years to 94 Years

Eligibility

Postmenopausal women who have attended the 20030216 (NCT00089791) study month 36 visit will be eligible to participate if they meet the inclusion and exclusion criteria given below. Inclusion Criteria

• Subjects must sign the informed consent before any study specific procedures are performed and agree to receive denosumab 60 mg subcutaneous injection every 6 months
• Subjects must not have discontinued investigational product during the 20030216 study and must have attended the 20030216 study month 36 visit
• Subjects must be re-consented prior to (or at) the 24 month visit for participation beyond month 24. Exclusion Criteria
• Permanently non-ambulatory subjects (use of an assistive device eg, cane, walker, etc. is permitted)
• Missed 2 or more investigational product doses during the 20030216 study
• Any disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures
• Developed sensitivity to mammalian cell derived drug products during the 20030216 study
• Unable to tolerate calcium supplementation during the last 6 months of participation in the 20030216 study (between the month 30 and month 36 20030216 study visits)
• Currently receiving any investigational product other than denosumab or having received any investigational product during the 20030216 study
• Current use of the following osteoporosis agents: bisphosphonates, calcitonin, fluoride, parathyroid hormone, selective estrogen receptor modulators, systemic oral or transdermal estrogen (except vaginal preparations and estrogen creams which are acceptable), strontium, or tibolone
• For bone biopsy sub-study subjects only: known or suspected sensitivity or contraindication to tetracycline derivatives

Related Conditions & MeSH terms

• Bone Diseases, Metabolic
• Osteopenia
• Osteoporosis

Intervention

Biological:
• Denosumab
Administered by subcutaneous injection once every 6 months.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

References & Publications (14)

Adachi JD, Bone HG, Daizadeh NS, Dakin P, Papapoulos S, Hadji P, Recknor C, Bolognese MA, Wang A, Lin CJF, Wagman RB, Ferrari S. Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study. BMC Musculoskelet Disord. 2017 Apr 27;18(1):174. doi: 10.1186/s12891-017-1520-6. — View Citation

Bilezikian JP, Lin CJF, Brown JP, Wang AT, Yin X, Ebeling PR, Fahrleitner-Pammer A, Franek E, Gilchrist N, Miller PD, Simon JA, Valter I, Zerbini CAF, Libanati C, Chines A. Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group. Osteoporos Int. 2019 Sep;30(9):1855-1864. doi: 10.1007/s00198-019-05020-8. Epub 2019 Jun 14. — View Citation

Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwinski E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017 Jul;5(7):513-523. doi: 10.1016/S2213-8587(17)30138-9. Epub 2017 May 22. — View Citation

Broadwell A, Chines A, Ebeling PR, Franek E, Huang S, Smith S, Kendler D, Messina O, Miller PD. Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease. J Clin Endocrinol Metab. 2021 Jan 23;106(2):397-409. doi: 10.1210/clinem/dgaa851. — View Citation

Cosman F, Huang S, McDermott M, Cummings SR. Multiple Vertebral Fractures After Denosumab Discontinuation: FREEDOM and FREEDOM Extension Trials Additional Post Hoc Analyses. J Bone Miner Res. 2022 Sep 11. doi: 10.1002/jbmr.4705. [Epub ahead of print] — View Citation

Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22. — View Citation

Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S, Valter I, Wagman RB, Yin X, Yue SV, Boivin G. Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2498-2509. doi: 10.1210/jc.2017-02669. — View Citation

Ferrari S, Butler PW, Kendler DL, Miller PD, Roux C, Wang AT, Huang S, Wagman RB, Lewiecki EM. Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3450-3461. doi: 10.1210/jc.2019-00271. — View Citation

Ferrari S, Eastell R, Napoli N, Schwartz A, Hofbauer LC, Chines A, Wang A, Pannacciulli N, Cummings SR. Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension. Bone. 2020 May;134:115268. doi: 10.1016/j.bone.2020.115268. Epub 2020 Feb 10. — View Citation

Ferrari S, Lewiecki EM, Butler PW, Kendler DL, Napoli N, Huang S, Crittenden DB, Pannacciulli N, Siris E, Binkley N. Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed. Bone. 2020 May;134:115287. doi: 10.1016/j.bone.2020.115287. Epub 2020 Feb 21. — View Citation

Ferrari S, Libanati C, Lin CJF, Brown JP, Cosman F, Czerwinski E, de Greg?rio LH, Malouf-Sierra J, Reginster JY, Wang A, Wagman RB, Lewiecki EM. Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment. J Bone Miner Res. 2019 Jun;34(6):1033-1040. doi: 10.1002/jbmr.3722. Epub 2019 May 29. — View Citation

Kendler DL, Chines A, Brandi ML, Papapoulos S, Lewiecki EM, Reginster JY, Muñoz Torres M, Wang A, Bone HG. The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporos Int. 2019 Jan;30(1):71-78. doi: 10.1007/s00198-018-4687-2. Epub 2018 Sep 22. — View Citation

Watts NB, Brown JP, Papapoulos S, Lewiecki EM, Kendler DL, Dakin P, Wagman RB, Wang A, Daizadeh NS, Smith S, Bone HG. Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. J Bone Miner Res. 2017 Jul;32(7):1481-1485. doi: 10.1002/jbmr.3119. Epub 2017 Apr 3. — View Citation

Watts NB, Grbic JT, Binkley N, Papapoulos S, Butler PW, Yin X, Tierney A, Wagman RB, McClung M. Invasive Oral Procedures and Events in Postmenopausal Women With Osteoporosis Treated With Denosumab for Up to 10 Years. J Clin Endocrinol Metab. 2019 Jun 1;104(6):2443-2452. doi: 10.1210/jc.2018-01965. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	84 months
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.	84 months
Primary	Number of Participants With Antibodies to Denosumab		Every 12 months through Month 84
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.	Baseline (of extension study) and months 12, 24, 36, 60 and 84
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.	Baseline (of extension study) and months 12, 24, 36, 60 and 84
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.	Baseline (of extension study) and months 12, 24, 36, 60 and 84
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.	Baseline (of extension study) and months 12, 24, 36, 60 and 84
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.	Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
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.	Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
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.	Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
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.	Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
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.	84 months
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.	84 months
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.	Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
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.	Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
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.	Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
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.	Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
Secondary	Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10		Baseline (of extension study) and day 10
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.	Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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).	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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).	Month 24 and month 84
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).	Month 24 and month 84
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).	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24 and month 84
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).	Month 24 and month 84
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.	Month 24 and month 84
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.	Month 24
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.	Month 84

External Links

•   AmgenTrials clinical trials website