Background/Purpose: Romosozumab is a
bone-forming agent that inhibits sclerostin. In a phase 2 study (NCT00896532), 12
months of romosozumab increased DXA bone mineral density (BMD) in
postmenopausal women with low bone mass (McClung et al. NEJM 2014). A
subset of these women underwent spine and hip quantitative computed tomography
(QCT) imaging, confirming the BMD gains (romosozumab vs teriparatide integral volumetric
BMD gains of 17.7% vs 12.9% at the spine and 4.1% vs 1.2% at the hip). To investigate
the effects of romosozumab on bone strength, we performed a finite element
analysis (FEA) on these QCT scans.

Methods: This international
randomized study enrolled postmenopausal women with lumbar spine, total hip, or
femoral neck T‑scores ≤–2.0 and ≥–3.5. In this analysis, subjects
received blinded subcutaneous romosozumab 210 mg monthly, placebo, or open-label
teriparatide (20 mcg daily). QCT scans were performed at the L1 and L2 lumbar vertebrae
and proximal femur at baseline and month 12. Subject-specific vertebral strength
for a simulated compression overload and femoral strength for a simulated
sideways fall were estimated blinded-to-treatment using a FDA-approved
non-linear 3D FEA (VirtuOst,
O.N. Diagnostics). Whole-bone and compartment strength changes were estimated. The
“cortical” compartment was defined as all bone within 2 mm and 3 mm of the
periosteal surface for the spine and hip, respectively, plus any high-density
bone (>1.0 g/cm³ of apparent density); the trabecular compartment
was defined as all other bone.

Results: At the spine,
romosozumab increased
strength from baseline by 27.3% at month 12, which was substantially higher than
placebo (–3.9%) and teriparatide (18.5%; Figure A). This
strengthening
effect was due to contributions from both the “cortical” and trabecular
compartments. At the hip, despite a small sample size for the romosozumab group,
strength increased compared with baseline for romosozumab (3.6%), but did not change
for placebo or teriparatide (Figure B). Again, both “cortical” and trabecular
compartment changes contributed to the overall strengthening observed with
romosozumab.

Conclusion: Romosozumab increased
strength at the spine and hip over 12 months, with strength improving in the “cortical” and
trabecular compartments at both sites. These strength improvements, documented using
a validated method for assessing fracture risk and monitoring treatment,
confirm and extend existing data and support romosozumab evaluation in the
ongoing phase 3 clinical program.