A Study to Evaluate the Effect of Romosozumab (AMG 785) on Bone Quality of the Forearm in Postmenopausal Women With Low Bone Mass

Phase 1

Completed

Conditions: Osteopenia

Interventions: Drug: Placebo
Drug: Romosozumab

Registration Number: NCT00950950

Lead Sponsor: Amgen

Brief Summary: The purpose of this study is to evaluate the effect of romosozumab on parameters of bone quality of the forearm using peripheral quantitative computed tomography (pQCT) following multiple subcutaneous dose administrations of romosozumab in postmenopausal women with low bone mass.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 24

Inclusion Criteria

Healthy females between 55 to 80 years of age
Postmenopausal females (based on medical history) defined as 12 continuous months of spontaneous amenorrhea
- Women 60 years of age and older will be considered postmenopausal
- Women 55-59 must have a serum follicle-stimulating hormone result > 40 mIU/mL and serum estradiol ≤ 20 pg/mL
Low bone mineral density (BMD), defined as a BMD T-score between -1.0 and -2.5 at the lumbar spine (L1-L4) and/or femoral neck
Weight ≤ 98 kg (216 lb) and/or height ≤ 196 cm (77 in)
25-hydroxyvitamin D ≥ 20 ng/mL at screening
Willing and able to take ≥ 500 mg calcium and ≥ 400 IU (but ≤ 1,000 IU) vitamin D daily

Exclusion Criteria

Osteoporosis, defined as a BMD T-score ≤ -2.5 at the lumbar spine or femoral neck
History of vertebral fracture, or fragility fracture of the wrist, humerus, hip or pelvis
Diagnosed with any condition that will affect bone metabolism
Subjects with fewer than 2 evaluable vertebrae; metal in forearms bilaterally that would not allow for at least one evaluable forearm
Administration of the following medications within 6 months before study drug administration. This includes all routes of administration, for example intranasal and topical skin patches, unless otherwise noted:
- Hormone replacement therapy [(eg, estrogen, estrogen-like compounds such as raloxifene). Infrequent use of estrogen vaginal creams (< 3 times per week) is allowed.]
- Calcitonin
- Parathyroid hormone (or any derivative)
- Glucocorticosteroids (inhaled or topical corticosteroids administered more than 2 weeks before the enrollment date are allowed)
- Anabolic steroids
- Calcitriol, and available analogues
Administration of daily, weekly, or monthly bisphosphonates (BP) unless meeting the following criteria:
- < 2 weeks of BP use requires a 2-month washout period
- 2 weeks to 3 months of BP use requires a 9-month washout period
- 3 to 6 months of BP use requires a 1-year washout period
- > 6 months of BP use requires a 3-year washout period;
Greatly differing levels of physical activity or constant levels of intense physical exercise during the 6 months before study drug administration
Known sensitivity to mammalian-derived drug preparations
Known to be hepatitis B surface antigen, hepatitis C virus or human Immunodeficiency virus (HIV) positive or a known diagnosis of acquired immunodeficiency syndrome (AIDS)
Any organic or psychiatric disorder, which, in the opinion of the investigator, poses a risk to subject safety and may prevent the subject from completing the study or interfere with the interpretation of the study results
Unavailable for follow-up assessment or any concerns for subject's compliance with the protocol procedures
Any other condition that might reduce the chance of obtaining data required by the protocol or that might compromise the ability to give truly informed consent
History or evidence of a clinically significant disorder, condition or disease that, in the opinion of the Investigator or Amgen physician would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
Clinically significant abnormality during the screening physical examination, electrocardiogram (ECG) or laboratory evaluation
Participation in another clinical study within 4 weeks of screening or within 5 times the half-life of the investigational agent in the other clinical study, if known
Has donated or lost 400 mL or more of blood or plasma within 8 weeks of study drug administration
Previous AMG 785 exposure

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants were randomized to receive matching placebo administered by subcutaneous injection once every 4 weeks (Q4W) for 3 months.
Romosozumab	Romosozumab	Participants were randomized to receive 3 mg/kg romosozumab administered by subcutaneous injection once every 4 weeks (Q4W) for 3 months.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Polar Cross-sectional Moment of Inertia at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	The polar moment of inertia is a geometric measurement used to predict bone quality, specifically the ability to resist torsion (twisting), and is highly correlated with fracture load at the distal radius. The polar cross-sectional moment of inertia was assessed using peripheral quantitative computed tomography (pQCT), a 3-dimensional imaging technology which can be used for volumetric analysis of appendicular skeletal sites such as the arms and the legs. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Total Bone Area at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Total bone area was assessed using peripheral quantitative computed tomography (pQCT), a 3-dimensional imaging technology which can be used for volumetric analysis of appendicular skeletal sites such as the arms and the legs. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Total Bone Mineral Content at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Total bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Cortical Bone Area at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Cortical bone area was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Periosteal Circumference at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Periosteal circumference was derived from pQCT measurements based on applying a circular ring model to the cortical shell. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Cortical Thickness at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Cortical thickness was derived from pQCT measurements based on applying a circular ring model to the cortical shell. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Polar Section Modulus at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Polar section modulus is a measurement of bone strength and was derived from pQCT measurements. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Polar Strength Strain Index at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	The polar strength strain index is a measurement of bone strength and was derived from pQCT measurements. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Axial Moment of Inertia at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Axial moment of inertia is an indicator of the ability of bone to resist bending, and was derived from pQCT measurements based on a circular ring model. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Total Bone Mineral Density at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Total bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Cortical Bone Mineral Content at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Cortical bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Cortical Bone Mineral Density at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Cortical bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Endocortical Circumference at the Distal Radius	Baseline and days 29, 57, 85, 127, and 169	Endocortical circumference was derived from pQCT measurements based on applying a circular ring model to the cortical shell. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Trabecular Bone Mineral Content at the Ultradistal Radius	Baseline and days 29, 57, 85, 127, and 169	Trabecular bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Trabecular Bone Mineral Density at the Ultradistal Radius	Baseline and days 29, 57, 85, 127, and 169	Trabecular bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Polar Strength Strain Index at the Ultradistal Radius	Baseline and days 29, 57, 85, 127, and 169	The polar strength strain index is a measurement of bone strength and was derived from pQCT measurements. The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Bone Mineral Density at the One-third Radius	Baseline and days 29, 57, 85, 127, and 169	Bone mineral density was assessed using dual energy x-ray absorptiometry (DXA). Scans were analyzed by a central reader.
Percent Change From Baseline in Bone Mineral Density at the Total Wrist	Baseline and days 29, 57, 85, 127, and 169	Bone mineral density was assessed using dual energy x-ray absorptiometry (DXA). Scans were analyzed by a central reader.
Percent Change From Baseline in Bone Mineral Density at the Total Lumbar Spine	Baseline and days 85 and 169	Bone mineral density was assessed using dual energy x-ray absorptiometry (DXA). Scans were analyzed by a central reader.
Percent Change From Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP)	Baseline and days 4, 15, 29, 57, 62, 71, 85, 99, 127, and 169
Percent Change From Baseline in Serum C-Telopeptide (sCTX)	Baseline and days 4, 15, 29, 57, 62, 71, 85, 99, 127, and 169
Time to Maximum Serum Concentration (Tmax) of Romosozumab	First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169	Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL.
Percent Change From Baseline in Total Bone Area at the Ultradistal Radius	Baseline and days 29, 57, 85, 127, and 169	Total bone area was assessed using peripheral quantitative computed tomography (pQCT), a 3-dimensional imaging technology which can be used for volumetric analysis of appendicular skeletal sites such as the arms and the legs. The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Total Bone Mineral Content at the Ultradistal Radius	Baseline and days 29, 57, 85, 127, and 169	Total bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Total Bone Mineral Density at the Ultradistal Radius	Baseline and days 29, 57, 85, 127, and 169	Total bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Percent Change From Baseline in Trabecular Bone Area at the Ultradistal Radius	Baseline and days 29, 57, 85, 127, and 169	Trabecular bone area was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader.
Maximum Serum Concentration (Cmax) of Romosozumab	First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169	Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL.
Area Under the Serum Concentration-time Curve From Time 0 to Tau (AUC0-28)	First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169	Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL. The area under the serum drug concentration-time curve from time zero to tau (tau = 28 days) (AUC0-28) was calculated by the linear trapezoidal method.
Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf)	Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169	Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL.
Apparent Clearance (CL/F) of Romosozumab	Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169	Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL.
Terminal Half-life (t1/2,z) of Romosozumab	Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169	Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL.
Accumulation Ratio	First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169	Accumulation ratio was calculated as the ratio of AUC0-28 after the last dose to AUC0-28 after the first dose.