Effects of DHEA and exercise on bone marrow fat in postmenopausal women - ABSTRACT
The proportion of the U.S. population older than 65 years will increase from 12.7% in 2000 to 20.3% in 2050,
and the number of fractures is expected to exceed 3 million by 2025 with associated costs in the order of $25.3
billion per year. DAMES is an ongoing clinical trial (NCT03227458) that aims to assess –for the first time–
changes in areal bone mineral density (aBMD) and fat-free mass (FFM) in response to therapy with the
adrenal steroid dehydroepiandrosterone (DHEA) alone and combined with bone-loading exercise (EX) in older
women with bone loss. The hormonal and mechanical strategies proposed in DAMES represent a low-cost
alternative treatment to improve bone quantity with a number of other health benefits not afforded by typical
pharmacological approaches. However, bone strength –the main determinant of bone fracture– is a function of
not only BMD and microstructure, but also of its microenvironment, including bone marrow fat (BMF). This in
an ancillary study to the DAMES clinical trial. Here, we propose to leverage the well-characterized cohort of
subjects, exercise training, clinical, laboratory and imaging data from DAMES, and add a small group of
controls to its three existing arms (DHEA only, EX+Placebo, and EX+DHEA) to investigate the effects of DHEA
therapy and EX on BMF in older women using advanced imaging, numerical engineering, and image analysis
techniques. In particular, we aim to determine in the lumbar spine and hip of older women with low bone mass
or moderate osteoporosis: 1) whether DHEA or EX leads to changes in BMF content; 2) whether BMF content
is associated with bone strength at baseline, and whether changes in BMF content are associated with
changes in bone strength, evaluating the impact of DHEA or EX on these associations; and 3) the spatial
distribution of changes in BMF content in response to DHEA or EX. BMF will be measured with chemical shift–
based water-fat separation magnetic resonance imaging, bone strength will be estimated with finite element
modeling from quantitative computed tomography scans, and differences in the spatial distribution of BMF
changes between groups will be assessed using voxel-based morphometry. Ultimately, we will leverage the
DAMES clinical trial to unveil new information to improve our understanding of DHEA and EX on bone quantity
and quality. The longitudinal assessments of bone quality in this ancillary proposal, with those of bone quantity
in the parent study, in women who have already lost bone mass is unprecedented. Understanding how
osteoporosis treatments –including exercise– act on BMF could lead to the generation of novel approaches for
fracture risk assessment, procedures for therapy monitoring, and treatments for bone loss.