Background/Purpose: Denosumab (a RANK ligand antibody) reduces remodeling, increases bone mineral density, and reduces cortical porosity in postmenopausal women with osteoporosis. In FREEDOM, denosumab treatment reduced the relative risk of hip fracture by 62% in those ≥ 75 years (Boonen et al, JCEM 2011). Bone strength at the hip, estimated by FEA from QCT scans, was significantly improved from baseline and compared with placebo (Keaveny et al, ASBMR 2010). To better characterize the changes, we used a novel cortical bone mapping technique on those same serial QCT scans, to determine the extent and distribution of mass and thickness changes at the proximal femur, a key skeletal site for fracture risk.

Methods: Eighty women age 74±5 years who participated in a FREEDOM substudy underwent hip QCT scanning at baseline, and months 12, 24, and 36 during denosumab (60 mg SC Q6M) or placebo treatment; all subjects received calcium and vitamin D supplementation. For each femur, in addition to overall cortical density, the distributions of cortical mass (in mg per unit cm² of periosteal surface) and thickness were measured in a blinded-to-treatment manner. Distributed measures were transferred to an average femur by first registering each individual femur to this surface. Statistical parametric mapping was used to calculate significance of denosumab or placebo effects at each time point in relation to baseline, and between treatments. Distributed results were visualised as a color map over the average femur.

Results: In denosumab-treated women, there was a progressive increase in cortical mass over time, reaching a difference vs placebo of ~6% at 3 years (p<0.0001) (Fig. 1). Approximately one-third of this increase was attributed to an increase in cortical density of 7.6±1.8 mg/cm³/year (p<0.0001), which in turn remained unchanged in placebo-treated subjects (p=0.62). With denosumab, cortical thickness was also significantly increased, which may represent in-filling of the cortical compartment. In contrast, average cortical mass and thickness decreased in subjects who received calcium and vitamin D alone. Mass color maps (Fig. 2) reveal the distribution of increases in cortical mass with denosumab, which were significant over an increasingly large area of the proximal femur.

Conclusion: In postmenopausal women with osteoporosis, administration of denosumab significantly and progressively increased cortical mass and thickness in regions of the proximal femur associated with hip fracture.