Grant Abstract: Effects of Equol, the most bioactive soy isoflavone, on bone microarchitecture, density, strength and turnover
Grant Number: 1R01AR085928-01A1
PI Name: Cauley
Project Title: Effects of Equol, the most bioactive soy isoflavone, on bone microarchitecture, density, strength and turnover
Abstract: The long-term goal of this project is to identify a safe and well tolerated non- pharmacologic therapy that may improve bone strength and reduce bone loss and turnover. The Arterial stiffness, Cognition and Equol (ACE) Trial is a double blind randomized controlled trial (RCT) that will test the effect of a 24-month intervention of 10 mg/day equol compared to placebo on cognitive decline, arterial stiffness and white matter disease among 371 subjects age 65-85 without dementia. We propose to extend ACE to include important skeletal measures of bone strength by High Resolution peripheral Quantitative Computed Tomography (HRpQCT) and bone turnover. We enrolled 276 of the participants into ACE-Bone: 194 of 231 enrolled in Pittsburgh and 82 of 105 enrolled at Wake Forest University. We will exclude 4 participants who were on osteoporosis medications so that our final sample size is 272, 87% of the parent ACE participants who were eligible. Soy isoflavones (SIF) are structurally similar to estradiol and are classified as phytoestrogens. SIF have demonstrated potential positive effects on bone strength. However, to date the effects of SIF on bone outcomes are inconclusive (7). Equol, a metabolite of daidzein, a common SIF transformed by the gut microbiome, is the most bioactive among all SIF. Equol is unique in its high affinity for ERβ. Of importance, equol is now available as a dietary supplement and we can directly assess the effects of equol. Administration of equol directly bypasses the need for the gut microbiome to convert isoflavones to equol. We propose the following specific aims: Aim 1: To determine the effect of equol on volumetric bone mineral density (BMD) and bone strength (failure load) globally and in the trabecular and cortical compartments separately. We hypothesize that equol will significantly improve vBMD and bone strength. Aim 2: To determine the effects of equol on bone formation, procollagen type I N-propeptide (P1NP), bone resorption, serum C-Terminal Cross-Linking Telopeptide (CTX) and sclerostin, a potent inhibitor of bone formation. We hypothesize that equol will decrease overall bone turnover. Exploratory Aim 3: To determine if the effect of equol on our skeletal outcome are mediated by effects on bone turnover and whether the anti-inflammatory properties of equol mediate the effect of equol on bone health. We hypothesize that the reductions in bone turnover and inflammatory markers will mediate the effects of equol on the skeleton. We secured internal pilot funds and obtained all baseline assessments. This R01 application will fund the completion of the 24-month follow-up visits and all analyses/assays to examine for the first time the treatment effects of equol on our novel skeletal outcomes. Overall Impact: Extending the ACE trial to include novel data on bone strength, microarchitecture, and BMD; and bone turnover is a cost-efficient opportunity to substantially increase our understanding of the clinical effects of equol – a biologically active dietary supplement that is safe and well tolerated. A positive signal could lead to trials testing whether equol improves BMD and bone strength and prevents bone loss and potentially fractures in high-risk subjects.
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