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.

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.

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