Romosozumab (AMG 785) in Postmenopausal Women With Low Bone Mineral Density

A Randomised, Placebo-controlled, Multi-dose Phase 2 Study to Determine the Efficacy, Safety and Tolerability of AMG 785 in the Treatment of Postmenopausal Women With Low Bone Mineral Density

The primary objective was to determine the effect of treatment with romosozumab versus placebo at month 12 on the percent change from baseline in bone mineral density (BMD) at the lumbar spine in postmenopausal women with low bone density.

Study Overview

• Status: Completed
• Conditions: Postmenopausal Osteoporosis; Low Bone Mineral Density
• Intervention / Treatment: Drug: Romosozumab; Drug: Placebo to Romosozumab; Drug: Denosumab; Drug: Placebo to Denosumab; Drug: Zoledronic acid; Drug: Alendronate; Drug: Teriparatide

Detailed Description

This study included a 24-month treatment phase followed by rerandomization to a 12-month extension phase with denosumab or placebo, followed by a 12-month retreatment phase with romosozumab, followed by a 24-month follow-on phase with zoledronic acid or no intervention.

• 24-month Romosozumab Treatment Phase (months 1 to 24): Participants were randomized in a 1:1:1:1:1:1:1:1 ratio to receive 1 of 5 double-blind dosing regimens of romosozumab or placebo or open-label alendronate (ALN) or open-label teriparatide (TPTD) for the first 12 months of the study. At month 12, participants in the romosozumab and placebo groups continued their assigned treatment for an additional 12 months, participants in the TPTD group ended study participation, and participants in the ALN group transitioned to receive romosozumab 140 mg subcutaneously (SC) every month (QM) for an additional 12 months (months 12 to 24).
• 12-month Denosumab Extension Phase (months 24 to 36): At the end of the 24-month romosozumab treatment phase, eligible participants were randomized 1:1 within their original treatment group to receive either denosumab or placebo every 6 months (Q6M) for 12 months.
• 12-month Romosozumab Retreatment Phase (months 36 to 48): From months 36 to 48, participants initially randomized to romosozumab or placebo received romosozumab 210 mg SC QM. Participants who initially received ALN ended their participation at month 36 and were not retreated with romosozumab.
• 24-month Follow-on Phase (months 48 to 72): At month 48, participants received 1 dose of zoledronic acid 5 mg intravenously or no intervention for an additional 24 months.

• Study Type: Interventional
• Enrollment (Actual): 419
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 53 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Ambulatory, postmenopausal women, aged ≥ 55 to ≤ 85
• Low BMD measured by dual energy X-ray absorptiometry (DXA) and assessed by the central imaging vendor (equivalent to T-scores between -2.0 and -3.5)

Exclusion Criteria:

• History of vertebral fracture, or fragility fracture of the wrist, humerus, hip or pelvis after age 50
• Untreated hyper- or hypothyroidism
• Current hyper- or hypoparathyroidism, hypo- or hypercalcemia
• Elevated transaminases
• Significantly impaired renal function
• Positive for: human immunodeficiency virus (HIV), hepatitis-C or hepatitis-B surface antigen
• Malignancy
• History of solid organ or bone marrow transplants
• Use of agents affecting bone metabolism
• Contraindicated or intolerant of alendronate therapy
• Contraindicated or intolerant of teriparatide therapy

Inclusion Criteria for the 12 month extension phase (Month 24 to 36):

- Normocalcemia at or after the Month 21 visit but before the Month 24 study visit

Exclusion Criteria for the 12 month extension phase (Month 24 to 36)

• Incidence of a clinical vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis during the initial 24 month treatment phase of the study
• A BMD loss of ≥ 7.0% from baseline at any time up to the Month 18 visit of the initial 24-month treatment phase
• Malignancy
• History of osteonecrosis of the jaw
• Use of proscribed medication during the initial 24 month treatment phase
• Contraindicated or intolerant of denosumab therapy

Inclusion Criteria for the 12 month re-treatment phase (Month 36 to 48)

• Albumin adjusted serum calcium of the most recent blood draw at or after the Month 30 visit but before the Month 36 study visit. Calcium repletion is permitted and central laboratory analysis of albumin adjusted serum calcium may be repeated before the Month 36 study visit
• Participation in Group A or B during initial 24 month treatment phase
• Subject has reached M36 of the study
• Appropriate written informed consent must be obtained

Exclusion Criteria for the 12 month re-treatment phase (Month 36 to 48)

• New malignancy
• Use of proscribed medication during the 12 month extension phase

Inclusion Criteria for the 24 month follow-on phase (Month 48 to 72) General inclusion criteria for participation

• Subject has reached month 48 of the study
• Appropriate written informed consent must be obtained Inclusion criteria for assignment to the no intervention group
• During the 24 month AMG 785 treatment phase, subject was assigned to any AMG 785 treatment group
• During the 12 month denosumab extension phase, subject was assigned to the denosumab treatment group Exclusion for the 24 month follow-on phase (Month 48 to 72)
• New malignancy
• Use of proscribed meds during the 12 month re-treatment phase
• Partial informed consent withdrawal and discontinuation of investigational product at any time up to month 48 visit
• Incidence of a clinical vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis during the initial 24 month treatment phase of the study
• BMD T-score of ≤ -2.5 at the lumbar spine, total hip, or femoral neck based on local read of the DXA scans at month 48
• Intolerance to zoledronic acid

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received placebo matching to romosozumab once a month (QM) or once every 3 months (Q3M) administered subcutaneously (SC) for up to 24 months. Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.	Drug: Placebo to Romosozumab; Administered by subcutaneous injection QM or Q3M.; Drug: Denosumab; Denosumab 60 mg administered by subcutaneous injection Q6M; Other Names: Prolia®; Drug: Placebo to Denosumab; Administered by subcutaneous injection Q6M; Drug: Zoledronic acid; Zoledronic acid 5 mg administered intravenously; Other Names: Aclasta
Active Comparator: Alendronate; Participants received open-label alendronate (ALN) 70 mg orally (PO) every week (QW) for 12 months. At month 12 participants transitioned to receive romosozumab 140 mg subcutaneously every month for an additional 12 months (months 12 to 24). Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. At month 36 participants ended study participation.	Drug: Romosozumab; Administered by subcutaneous injection; Other Names: AMG 785; EVENITY™; Drug: Denosumab; Denosumab 60 mg administered by subcutaneous injection Q6M; Other Names: Prolia®; Drug: Placebo to Denosumab; Administered by subcutaneous injection Q6M; Drug: Alendronate; Administered orally once a week; Other Names: Fosamax
Active Comparator: Teriparatide; Participants received open-label teriparatide 20 μg subcutaneously every day (QD) for 12 months. At month 12 participants ended study participation.	Drug: Teriparatide; Teriparatide 20 μg administered by subcutaneous injection once a day; Other Names: Forsteo
Experimental: Romosozumab 70 mg QM; Participants received double-blind romosozumab 70 mg subcutaneously every month for 24 months. Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.	Drug: Romosozumab; Administered by subcutaneous injection; Other Names: AMG 785; EVENITY™; Drug: Denosumab; Denosumab 60 mg administered by subcutaneous injection Q6M; Other Names: Prolia®; Drug: Placebo to Denosumab; Administered by subcutaneous injection Q6M; Drug: Zoledronic acid; Zoledronic acid 5 mg administered intravenously; Other Names: Aclasta
Experimental: Romosozumab 140 mg Q3M; Participants received double-blind romosozumab 140 mg subcutaneously once every 3 months for 24 months. Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.	Drug: Romosozumab; Administered by subcutaneous injection; Other Names: AMG 785; EVENITY™; Drug: Denosumab; Denosumab 60 mg administered by subcutaneous injection Q6M; Other Names: Prolia®; Drug: Placebo to Denosumab; Administered by subcutaneous injection Q6M; Drug: Zoledronic acid; Zoledronic acid 5 mg administered intravenously; Other Names: Aclasta
Experimental: Romosozumab 140 mg QM; Participants received double-blind romosozumab 140 mg QM subcutaneously for 24 months. Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.	Drug: Romosozumab; Administered by subcutaneous injection; Other Names: AMG 785; EVENITY™; Drug: Denosumab; Denosumab 60 mg administered by subcutaneous injection Q6M; Other Names: Prolia®; Drug: Placebo to Denosumab; Administered by subcutaneous injection Q6M; Drug: Zoledronic acid; Zoledronic acid 5 mg administered intravenously; Other Names: Aclasta
Experimental: Romosozumab 210 mg Q3M; Participants received double-blind romosozumab 210 mg Q3M subcutaneously for 24 months. Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.	Drug: Romosozumab; Administered by subcutaneous injection; Other Names: AMG 785; EVENITY™; Drug: Denosumab; Denosumab 60 mg administered by subcutaneous injection Q6M; Other Names: Prolia®; Drug: Placebo to Denosumab; Administered by subcutaneous injection Q6M; Drug: Zoledronic acid; Zoledronic acid 5 mg administered intravenously; Other Names: Aclasta
Experimental: Romosozumab 210 mg QM; Participants received double-blind romosozumab 210 mg QM subcutaneously for 24 months. Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.	Drug: Romosozumab; Administered by subcutaneous injection; Other Names: AMG 785; EVENITY™; Drug: Denosumab; Denosumab 60 mg administered by subcutaneous injection Q6M; Other Names: Prolia®; Drug: Placebo to Denosumab; Administered by subcutaneous injection Q6M; Drug: Zoledronic acid; Zoledronic acid 5 mg administered intravenously; Other Names: Aclasta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline at Month 12 in BMD at the Lumbar Spine	Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader.	Baseline to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline at Month 6 in BMD at the Lumbar Spine	Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to month 6 was analyzed using a linear mixed effects model with the percent change from baseline to month 6 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables.	Baseline to 6 months
Percent Change From Baseline at Month 6 in BMD of the Total Hip	Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to month 6 was analyzed using a linear mixed effects model with the percent change from baseline to month 6 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables.	Baseline to 6 months
Percent Change From Baseline at Month 6 in BMD of the Femoral Neck	Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to month 6 was analyzed using a linear mixed effects model with the percent change from baseline to month 6 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables.	Baseline to 6 months
Percent Change From Baseline at Month 12 in BMD of the Total Hip	Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to 12 months in BMD was analyzed using a linear mixed effects model with the percent change from baseline to month 12 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables.	Baseline to 12 months
Percent Change From Baseline at Month 12 in BMD of the Femoral Neck	Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to 12 months in BMD was analyzed using a linear mixed effects model with the percent change from baseline to month 12 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables.	Baseline to 12 months
Percent Change From Baseline at Month 12 in BMD of the Distal Radius	Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline in distal radius BMD was analyzed using an analysis of covariance (ANCOVA) model with the percent change from baseline to Month 12 in DXA BMD as dependent variable, baseline BMD value, machine type, interaction of baseline BMD and machine type, treatment (categorical) and geographic region as the independent class variables.	Baseline to 12 months
Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP)	Percent change from baseline in the bone turnover marker (BTM) P1NP was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline.	Baseline and months 1, 3, 6, 9, and 12
Percent Change From Baseline in Type 1 Collagen C-telopeptide (CTX)	Percent change from baseline in the bone turnover marker (BTM) CTX was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline.	Baseline and months 1, 3, 6, 9, and 12
Percent Change From Baseline in Osteocalcin	Percent change from baseline in the bone turnover marker (BTM) osteocalcin was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline.	Baseline and months 1, 3, 6, 9, and 12
Percent Change From Baseline in Bone-specific Alkaline Phosphatase (BSAP)	Percent change from baseline in the bone turnover marker (BTM) BSAP was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline.	Baseline and months 1, 3, 6, 9, and 12

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Genant HK, Engelke K, Bolognese MA, Mautalen C, Brown JP, Recknor C, Goemaere S, Fuerst T, Yang YC, Grauer A, Libanati C. Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass. J Bone Miner Res. 2017 Jan;32(1):181-187. doi: 10.1002/jbmr.2932. Epub 2016 Sep 20.
• Keaveny TM, Crittenden DB, Bolognese MA, Genant HK, Engelke K, Oliveri B, Brown JP, Langdahl BL, Yan C, Grauer A, Libanati C. Greater Gains in Spine and Hip Strength for Romosozumab Compared With Teriparatide in Postmenopausal Women With Low Bone Mass. J Bone Miner Res. 2017 Sep;32(9):1956-1962. doi: 10.1002/jbmr.3176. Epub 2017 Jun 26.
• Kendler DL, Bone HG, Massari F, Gielen E, Palacios S, Maddox J, Yan C, Yue S, Dinavahi RV, Libanati C, Grauer A. Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab. Osteoporos Int. 2019 Dec;30(12):2437-2448. doi: 10.1007/s00198-019-05146-9. Epub 2019 Oct 18.
• McClung MR, Brown JP, Diez-Perez A, Resch H, Caminis J, Meisner P, Bolognese MA, Goemaere S, Bone HG, Zanchetta JR, Maddox J, Bray S, Grauer A. Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study. J Bone Miner Res. 2018 Aug;33(8):1397-1406. doi: 10.1002/jbmr.3452. Epub 2018 May 22.
• McClung MR, Bolognese MA, Brown JP, Reginster JY, Langdahl BL, Maddox J, Shi Y, Rojeski M, Meisner PD, Grauer A. A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab. Osteoporos Int. 2020 Nov;31(11):2231-2241. doi: 10.1007/s00198-020-05502-0. Epub 2020 Jul 4.
• McClung MR, Bolognese MA, Brown JP, Reginster JY, Langdahl BL, Shi Y, Timoshanko J, Libanati C, Chines A, Oates MK. Skeletal responses to romosozumab after 12 months of denosumab. JBMR Plus. 2021 Jun 3;5(7):e10512. doi: 10.1002/jbm4.10512. eCollection 2021 Jul.
• Poole KE, Treece GM, Pearson RA, Gee AH, Bolognese MA, Brown JP, Goemaere S, Grauer A, Hanley DA, Mautalen C, Recknor C, Yang YC, Rojeski M, Libanati C, Whitmarsh T. Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density. J Bone Miner Res. 2022 Feb;37(2):256-264. doi: 10.1002/jbmr.4465. Epub 2021 Dec 16.
• McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster JY, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang YC, Libanati C, Bone HG. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014 Jan 30;370(5):412-20. doi: 10.1056/NEJMoa1305224. Epub 2014 Jan 1.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2009
• Primary Completion (Actual): February 21, 2011
• Study Completion (Actual): February 18, 2016

Study Registration Dates

• First Submitted: May 7, 2009
• First Submitted That Met QC Criteria: May 7, 2009
• First Posted (Estimate): May 11, 2009

Study Record Updates

• Last Update Posted (Actual): September 22, 2022
• Last Update Submitted That Met QC Criteria: September 9, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Osteoporosis; Bone Diseases, Metabolic; Osteoporosis, Postmenopausal; Physiological Effects of Drugs; Immunologic Factors; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antibodies, Monoclonal; Alendronate; Zoledronic Acid; Teriparatide; Denosumab
• Other Study ID Numbers: 20060326; 2008-005991-28 (EudraCT Number)