Determine the Efficacy, Safety and Tolerability of Denosumab (AMG 162) in the Treatment of Postmenopausal Women With Low Bone Mineral Density

A Randomized, Double-Blind, Placebo-controlled, Multi-dose Phase 2 Study to Determine the Efficacy, Safety and Tolerability of AMG 162 in the Treatment of Postmenopausal Women With Low Bone Mineral Density

To determine the effect of denosumab treatment compared with placebo over 12 months on bone mineral density (BMD) of the lumbar spine in postmenopausal women with low BMD. The clinical hypothesis is that denosumab subcutaneous injections administered every 3 or 6 months for 12 months will significantly increase lumbar spine bone mineral density and will be well tolerated.

Study Overview

• Status: Completed
• Conditions: Low Bone Mineral Density
• Intervention / Treatment: Drug: Placebo; Drug: Denosumab; Drug: Alendronate

• Study Type: Interventional
• Enrollment (Actual): 412
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria

• women not more than 80 years of age on date of randomization
• ≥ 1 year postmenopausal on date of randomization
• ambulatory
• if ≤ 60 years of age, or had or would require a bilateral oophorectomy, serum follicle stimulating hormone (FSH) > 50 mU/mL or serum estradiol < 20 pg/mL
• low BMD (BMD T-score ≤ -1.8 at any 1 of the following sites: lumbar spine, femoral neck, or total hip; BMD T-scores must not have been < -4.0 at the lumbar spine or - 3.5 at the femoral neck or total hip)
• before any study-specific procedure, including the screening dual X-ray absorptiometry (DXA) scan, gave informed consent for participation in the study.

Exclusion Criteria

• fluoride treatment for osteoporosis within the 2 years before the enrollment date
• bisphosphonate use within the 12 months before the enrollment date

• administration of the following medications within the 6 months before the enrollment date

  • tibolone
  • Parathyroid hormone (PTH) (or any derivative)
  • systemic glucocorticosteroids (> 5 mg oral prednisone equivalent per day for > 10 days)
  • inhaled corticosteroids (> 2000 μg per day for > 10 days)
  • anabolic steroids or testosterone

• administration of the following medications within the 3 months before the enrollment date

  • systemic hormone replacement therapy
  • selective estrogen receptor modulators
  • calcitonin
  • calcitriol
• current hyper- or hypothyroidism (allowed if stable on thyroid replacement therapy and thyroid-stimulating hormone was within the normal range)
• current hyper- or hypoparathyroidism
• albumin-adjusted serum calcium < 8.5 mg/dL (< 2.125 mol/L)
• osteomalacia
• rheumatoid arthritis
• Paget's disease
• malignancy within the 5 years before enrollment (except cervical carcinoma in situ or basal cell carcinoma, which were acceptable)
• renal disease; ie, creatinine clearance ≤ 35 mL/min
• any bone disease, other than osteoporosis, which could interfere with the interpretation of the findings (eg, osteogenesis imperfecta or osteopetrosis)
• malabsorption syndrome
• weight, height, or girth that could preclude accurate DXA measurements
• < 2 lumbar vertebrae (L1 through L4) evaluable by DXA
• recent long bone fracture (within 6 months)
• osteoporotic-related fracture (ie, crush or wedge vertebral fracture or hip fracture) known or suspected to have occurred within 2 years of randomization
• > 1 single, grade 1 vertebral fracture
• currently enrolled in or had participated within the previous 30 days in other investigational device or drug trial(s) (For some trials, this may have been allowed after discussion and written approval from Amgen.)
• known sensitivity to mammalian-derived drug preparations (eg, Herceptin®)
• any organic or psychiatric disorder, serum chemistry, or hematology that, in the opinion of the investigator, could have prevented the subject from completing the study or have interfered with the interpretation of the study results
• self-reported alcohol or drug abuse within the previous 12 months
• any disorder that compromised the ability to give truly informed consent for participation in the study
• previous administration of denosumab
• known sensitivity or contraindication to alendronate
• known sensitivity or contraindication to tetracycline derivatives (subjects in the biopsy substudy only).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received double-blind subcutaneous (SC) placebo injections every 3 months until month 21 and then placebo SC injections once every 6 months from Month 24 through Month 42.	Drug: Placebo; Placebo subcutaneous injection
Experimental: Denosumab 6 mg every 3 months; Participants received denosumab 6 mg SC every 3 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42.	Drug: Denosumab; Denosumab for subcutaneous injection; Other Names: Prolia; AMG 162
Experimental: Denosumab 14 mg every 3 months; Participants received denosumab 14 mg SC every 3 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42.	Drug: Denosumab; Denosumab for subcutaneous injection; Other Names: Prolia; AMG 162
Experimental: Denosumab 30 mg every 3 months; Participants received denosumab 30 mg SC every 3 months until Month 21 then placebo SC every 6 months at Month 24 and Month 30 and then denosumab 60 mg SC every 6 months at Month 36 and Month 42.	Drug: Denosumab; Denosumab for subcutaneous injection; Other Names: Prolia; AMG 162
Experimental: Denosumab 14 mg every 6 months; Participants received denosumab 14 mg SC every 6 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42.	Drug: Denosumab; Denosumab for subcutaneous injection; Other Names: Prolia; AMG 162
Experimental: Denosumab 60 mg every 6 months; Participants received denosumab 60 mg SC every 6 months until Month 42.	Drug: Denosumab; Denosumab for subcutaneous injection; Other Names: Prolia; AMG 162
Experimental: Denosumab 100 mg every 6 months; Participants received denosumab 100 mg SC every 6 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42.	Drug: Denosumab; Denosumab for subcutaneous injection; Other Names: Prolia; AMG 162
Experimental: Denosumab 210 mg every 6 months; Participants received denosumab 210 mg SC every 6 months until Month 21 and then placebo every 6 months from Month 24 through Month 42.	Drug: Denosumab; Denosumab for subcutaneous injection; Other Names: Prolia; AMG 162
Active Comparator: Alendronate 70 mg; Participants received open-label alendronate 70 mg tablets orally once a week through Month 24. From Month 24 to Month 48 participants received no treatment.	Drug: Alendronate; Alendronate 70 mg tablets; Other Names: Fosamax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 for the Placebo and Denosumab Arms	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum CTX Percent Change From Baseline at Month 12	Serum C-Telopeptide (CTX). Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and Month 12
Urine NTX/Creatinine Percent Change From Baseline at Month 12	Urinary N-telopeptide (uNTX)/Creatinine. Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and Month 12
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 for the Alendronate Arm	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and Month 12
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 24	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 24 calculated using ((Month 24 value - Baseline value) / Baseline value ) x 100.	Baseline and 24 months
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 36	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 36 calculated using ((Month 36 value - Baseline value) / Baseline value ) x 100.	Baseline and 36 months
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 42	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 42 calculated using ((Month 42 value - Baseline value) / Baseline value ) x 100.	Baseline and 42 months
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 48	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 48 calculated using ((Month 48 value - Baseline value) / Baseline value ) x 100.	Baseline and 48 months
Serum CTX Percent Change From Baseline at Month 24	Serum C-Telopeptide (CTX). Percent change from Baseline to Month 24 calculated using ((Month 24 value - Baseline value) / Baseline value ) x 100.	Baseline and 24 months
Serum CTX Percent Change From Baseline at Month 36	Serum C-Telopeptide (CTX). Percent change from Baseline to Month 36 calculated using ((Month 36 value - Baseline value) / Baseline value ) x 100.	Baseline and 36 months
Serum CTX Percent Change From Baseline at Month 42	Serum C-Telopeptide (CTX). Percent change from Baseline to Month 42 calculated using ((Month 42 value - Baseline value) / Baseline value ) x 100.	Baseline and 42 months
Serum CTX Percent Change From Baseline at Month 48	Serum C-Telopeptide (CTX). Percent change from Baseline to Month 48 calculated using ((Month 48 value - Baseline value) / Baseline value ) x 100.	Baseline and 48 months
Urine NTX/Creatinine Percent Change From Baseline at Month 24	Urinary N-telopeptide (uNTX)/Creatinine. Percent change from Baseline to Month 24 calculated using ((Month 24 value - Baseline value) / Baseline value ) x 100.	Baseline and 24 months
Urine NTX/Creatinine Percent Change From Baseline at Month 36	Urinary N-telopeptide (uNTX)/Creatinine. Percent change from Baseline to Month 36 calculated using ((Month 36 value - Baseline value) / Baseline value ) x 100.	Baseline and 36 months
Urine NTX/Creatinine Percent Change From Baseline at Month 42	Urinary N-telopeptide (uNTX)/Creatinine. Percent change from Baseline to Month 42 calculated using ((Month 42 value - Baseline value) / Baseline value ) x 100.	Baseline and 42 months
Urine NTX/Creatinine Percent Change From Baseline at Month 48	Urinary N-telopeptide (uNTX)/Creatinine. Percent change from Baseline to Month 48 calculated using ((Month 48 value - Baseline value) / Baseline value ) x 100.	Baseline and 48 months
Total Hip Bone Mineral Density Percent Change From Baseline at Month 12	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and 12 months
Total Hip Bone Mineral Density Percent Change From Baseline at Month 24	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 24 calculated using ((Month 24 value - Baseline value) / Baseline value ) x 100.	Baseline and 24 months
Total Hip Bone Mineral Density Percent Change From Baseline at Month 36	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 36 calculated using ((Month 36 value - Baseline value) / Baseline value ) x 100.	Baseline and 36 months
Total Hip Bone Mineral Density Percent Change From Baseline at Month 42	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 42 calculated using ((Month 42 value - Baseline value) / Baseline value ) x 100.	Baseline and 42 months
Total Hip Bone Mineral Density Percent Change From Baseline at Month 48	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 48 calculated using ((Month 48 value - Baseline value) / Baseline value ) x 100.	Baseline and 48 months
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and 12 months
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 24	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 24 calculated using ((Month 24 value - Baseline value) / Baseline value ) x 100.	Baseline and 24 months
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 36	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 36 calculated using ((Month 36 value - Baseline value) / Baseline value ) x 100.	Baseline and 36 months
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 42	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 42 calculated using ((Month 42 value - Baseline value) / Baseline value ) x 100.	Baseline and 42 months
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 48	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 48 calculated using ((Month 48 value - Baseline value) / Baseline value ) x 100.	Baseline and 48 months
Total Body Bone Mineral Density Percent Change From Baseline at Month 12	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and 12 months
Total Body Bone Mineral Density Percent Change From Baseline at Month 24	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 24 calculated using ((Month 24 value - Baseline value) / Baseline value ) x 100.	Baseline and 24 months
Total Body Bone Mineral Density Percent Change From Baseline at Month 36	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 36 calculated using ((Month 36 value - Baseline value) / Baseline value ) x 100.	Baseline and 36 months
Total Body Bone Mineral Density Percent Change From Baseline at Month 42	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 42 calculated using ((Month 42 value - Baseline value) / Baseline value ) x 100.	Baseline and 42 months
Total Body Bone Mineral Density Percent Change From Baseline at Month 48	Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 48 calculated using ((Month 48 value - Baseline value) / Baseline value ) x 100.	Baseline and 48 months
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 12	Bone specific alkaline phosphatase (BSAP). Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.	Baseline and 12 months
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 24	Bone specific alkaline phosphatase (BSAP). Percent change from Baseline to Month 24 calculated using ((Month 24 value - Baseline value) / Baseline value ) x 100.	Baseline and 24 months
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 36	Bone specific alkaline phosphatase (BSAP). Percent change from Baseline to Month 36 calculated using ((Month 36 value - Baseline value) / Baseline value ) x 100.	Baseline and 36 months
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 42	Bone specific alkaline phosphatase (BSAP). Percent change from Baseline to Month 42 calculated using ((Month 42 value - Baseline value) / Baseline value ) x 100.	Baseline and 42 months
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 48	Bone specific alkaline phosphatase (BSAP). Percent change from Baseline to Month 48 calculated using ((Month 48 value - Baseline value) / Baseline value ) x 100.	Baseline and 48 months

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Beck TJ, Lewiecki EM, Miller PD, Felsenberg D, Liu Y, Ding B, Libanati C. Effects of denosumab on the geometry of the proximal femur in postmenopausal women in comparison with alendronate. J Clin Densitom. 2008 Jul-Sep;11(3):351-9. doi: 10.1016/j.jocd.2008.04.001. Epub 2008 May 20.
• Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, Wang A, Siddhanti S, Fitzpatrick LA; AMG 162 Bone Loss Study Group. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007 Dec;22(12):1832-41. doi: 10.1359/jbmr.070809.
• McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ; AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006 Feb 23;354(8):821-31. doi: 10.1056/NEJMoa044459.
• Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.
• Peterson MC, Riggs MM. A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. Bone. 2010 Jan;46(1):49-63. doi: 10.1016/j.bone.2009.08.053. Epub 2009 Sep 2.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start: May 1, 2002
• Primary Completion (Actual): April 1, 2007
• Study Completion (Actual): June 1, 2007

Study Registration Dates

• First Submitted: August 6, 2002
• First Submitted That Met QC Criteria: August 6, 2002
• First Posted (Estimate): August 7, 2002

Study Record Updates

• Last Update Posted (Estimate): September 18, 2013
• Last Update Submitted That Met QC Criteria: September 6, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: osteoporosis; bone loss
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Physiological Effects of Drugs; Bone Density Conservation Agents; Alendronate; Denosumab
• Other Study ID Numbers: 20010223