Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab

Abstract

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by -4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis.

Keywords: DENOSUMAB; FINITE ELEMENT ANALYSIS; HIP STRENGTH; OSTEOPOROSIS; SPINE STRENGTH.

Figure 1

Example of finite element models for one subject at baseline. The full three-dimensional model is shown, with a schematic of how the loads are applied (through center of head at hip; distributed evenly for spine). The models for estimating strength changes associated with changes in only the trabecular and “cortical” compartments are also shown (thin 2D sections only). Our definition of the “cortical” compartment included all obvious cortical bone (defined as bone having an apparent BMD of >1.0 g/cm³) plus any other bone within a fixed distance of the periosteal surface (3 mm for the hip; 2 mm for the spine); the trabecular compartment was defined as all of the remaining trabecular bone.

Figure 2

Mean percentage change from baseline in strength for the hip (A) and spine (B), as estimated by the finite element analysis (FEA). *p < 0.0001 versus both baseline and placebo; ^†p < 0.0001 versus 12 months; ^‡p < 0.005 versus baseline; ^§p < 0.05 versus 12 months. Least-squares means ± 95% confidence intervals.

Figure 3

Mean percentage change in whole bone, trabecular, and “cortical” compartment strength for the hip (A) and spine (B), as estimated by the finite element analysis (FEA), at 36 months. *p < 0.0001 versus both baseline and placebo; ^†p < 0.01 versus 12 months; ^‡p < 0.005 versus baseline; ^§p < 0.05 versus 12 months. Least-squares means ± 95% confidence intervals.

Figure 4

Relationship between changes from baseline in hip and spine strength (in Newtons), as estimated by the finite element analysis (FEA), in denosumab (closed circles) and placebo (open circles) subjects.