Abstract
Women with osteoporosis treated for 36 months with twice-yearly injections of denosumab sustained fewer hip fractures compared with placebo. Treatment might improve femoral bone at locations where fractures typically occur. To test this hypothesis, we used 3D cortical bone mapping of postmenopausal women with osteoporosis to investigate the timing and precise location of denosumab versus placebo effects in the hips. We analyzed clinical computed tomography scans from 80 female participants in FREEDOM, a randomized trial, wherein half of the study participants received subcutaneous denosumab 60 mg twice yearly and the others received placebo. Cortical 3D bone thickness maps of both hips were created from scans at baseline, 12, 24, and 36 months. Cortical mass surface density maps were also created for each visit. After registration of each bone to an average femur shape model followed by statistical parametric mapping, we visualized and quantified statistically significant treatment effects. The technique allowed us to pinpoint systematic differences between denosumab and control and to display the results on a 3D average femur model. Denosumab treatment led to an increase in femoral cortical mass surface density and thickness, already evident by the third injection (12 months). Overall, treatment with denosumab increased femoral cortical mass surface density by 5.4% over 3 years. One-third of the increase came from increasing cortical density, and two-thirds from increasing cortical thickness, relative to placebo. After 36 months, cortical mass surface density and thickness had increased by up to 12% at key locations such as the lateral femoral trochanter versus placebo. Most of the femoral cortex displayed a statistically significant relative difference by 36 months. Osteoporotic cortical bone responds rapidly to denosumab therapy, particularly in the hip trochanteric region. This mechanism may be involved in the robust decrease in hip fractures observed in denosumab-treated women at increased risk of fracture.
Highlights
Combating the rising epidemic of hip fractures is a key goal in musculoskeletal research
We tested the hypothesis that denosumab treatment of women with osteoporosis would improve cortical bone in regions of focal thinning and, begin to explain the 8.4% increase in overall femur strength with treatment shown by modeling
We found that by 36 months, most of the femoral cortex of denosumab‐treated women displayed a statistically significant increase in cortical mass surface density, but smaller foci were already detectable by 12 months
Summary
Combating the rising epidemic of hip fractures is a key goal in musculoskeletal research. Women treated with denosumab injections sustained significantly fewer hip fractures than those receiving placebo.[1] The difference in hip fracture events appeared early (Fig. 1), persisted, and was noteworthy in subjects aged 75 years and older.[1] Most hip fractures in clinical practice occur because of falls onto the greater trochanter,(2) and when femurs are subjected to similar conditions in the lab, the failure of very small (less than 6.4% of all bone tissue) foci of bone are sufficient to lead to catastrophic fracture.[3] When FREEDOM study participants’ femurs were subjected to sideways fall simulations, denosumab increased calculated femoral strength by 8.4% over 3 years,(4) perhaps because of focal changes in bone structure. We investigated the effects of denosumab treatment on cortical bone throughout the proximal femur, paying particular attention to the specific locations where hip fractures have been found to occur during laboratory simulations.[5,6,7]
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