DHEA augmentation of musculoskeletal adaptations to exercise in older women

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Exercise (Ex) is recommended for postmenopausal women to maintain or increase areal bone mineral density (aBMD), to improve muscular fitness and balance, and ultimately to prevent fractures. During exercise, joint- reaction and ground-reaction forces contribute to strain signals that are transduced via a mechanostat to osteocytes, causing region-specific adaptations in bone tissue. However, age-related declines in anabolic adrenal, gonadal, and somatotropic hormones may blunt this and other musculoskeletal adaptations to Ex. Dehydroepiandrosterone (DHEA) is the major source of estrogen (E2) and testosterone (T) in postmenopausal women but adrenal DHEA production declines with age. E2 is essential for strain mechanotransduction and reduces bone resorption whereas T promotes bone formation, is anti-resorptive to bone, and anabolic to skeletal muscle. In older women, DHEA therapy (50 mg/day) increased serum E2 and T, lumbar spine aBMD, and fat-free mass (FFM, a surrogate for skeletal muscle mass). We propose that DHEA therapy, by providing androgenic and estrogenic hormonal support, will augment the effects of bone-loading exercise on aBMD and FFM in women with low aBMD (i.e., osteopenia). This population is our focus because low aBMD, an indicator of fracture risk, may be reversible. The mechanical stimulus will be progressive resistance exercises and jumping to impart moderate- to high-intensity joint- and ground-reaction forces on bone, 3 times weekly for 36 weeks. Our overall objective is to determine if the musculoskeletal adaptations to progressive, bone-loading Ex can be significantly augmented in postmenopausal women with low aBMD by restoring serum DHEAS to youthful levels. Aims 1 and 2 will determine whether DHEA augments the effects of Ex on changes in lumbar spine aBMD and FFM, respectively. We hypothesize that the increases in aBMD and FFM will be greater in Ex+DHEA than Ex+Placebo (PL) or DHEA alone. Secondarily, we will determine the effects of DHEA with or without Ex on changes in trabecular and cortical volumetric bone density (vBMD) and bone strength of the lumbar spine and proximal femur. These outcomes are essential to understanding bone properties that contribute to fracture resistance. Changes in serum sex hormones and bone turnover markers will be investigated as potential mediators of the changes in aBMD, vBMD, bone strength, and FFM. We will determine whether the changes in FFM mediate changes in aBMD, vBMD, or bone strength. To achieve these aims, postmenopausal women aged 60-80 years with low bone mass (hip or spine T-scores < -1.0 and > - 2.5) will be randomized to Ex+DHEA, Ex+PL, or DHEA alone for 36 weeks. Given the tightly integrated functional relation of skeletal muscle and bone, we are keenly interested in therapies that simultaneously benefit both systems. Anabolic therapies that increase aBMD and impart fracture resistance, rather than slowing bone loss, are needed for older women. Ex+DHEA includes 3 anabolic mechanisms – mechanical strain, estrogenic effects on strain signaling and bone metabolism, and androgenic stimulation of muscle and bone.