A Prevention Strategy for the Indication of Prune Consumption in Perimenopausal Females: Can Prunes Attenuate Bone loss?

Given that women spend at least one-third of their lifespan after menopause, strategies that improve the long-term health of women and engage a 'prevention' strategy to improve health are warranted and represent opportunities for high impact and high return on investment[2]. For example, after menopause one in two women will suffer a fragility fracture in their lifetime, [2, 3] and the mortality rate after a hip fracture is as high as 25% [3-5]. Moreover, since osteoporosis-related treatment costs more than $100 billion worldwide, strategies that focus on the prevention of osteoporosis-related fragility fractures are warranted [2]. As such, the prevention of bone loss, osteoporosis and its related fractures is much preferred over treatment of osteoporosis given the high costs, negative side effects, and poor compliance to pharmacological treatment regimens[2, 3]. Therefore, research addressing the optimization of the health of perimenopausal women to delay chronic disease is very much necessary and represents our overall objective of this proposal. Given the high mortality rate of hip fractures [3-5], our intervention may potentially save women's lives while reducing a significant healthcare burden. Our first goal is to change the course of bone loss during a very specific and opportunistic intervention window, i.e., the transmenopausal window. This window of intervention is opportunistic because women lose more bone at the hip and spine than at any other time; that is, as much as 6% and 7% at the hip and spine, respectively [6-8]. In fact, the amount of bone loss during this three-year transmenopausal window that initiates late perimenopause is greater than the amount of bone loss observed during the postmenopause window, when the latter is defined as 2 to 5 years after the final menstrual period (FMP)[6, 8]. The stages of menopause as defined by the STRAW+10 investigators [9-12] and those stages that comprise the transmenopause period , along with the hassociated bone loss. As such, the proposed work is novel, innovative, and can potentially delay the serious effects of osteoporotic bone loss and associated fractures, to which transmenopausal bone loss significantly contributes [6-8]. When one considers that as of 2021, there were approximately 1.02 billion women over 50 years of age worldwide with an estimated 1.2 billion women over the age of 50 by 2030, accounting for 26% of all women worldwide [13-15], the potential impact of our project is substantial. Indeed, our project may affect the long-term picture of bone health for millions of women by delaying or attenuating the acceleration of bone loss during the transmenopause period. Moreover, since osteoporosis affects millions of women worldwide [2, 3], this project has the potential to offset the devasting long-term effects of accelerated bone loss during transmenopause that is associated with osteoporosis.Our second goal is to test whether prunes are effective in attenuating the rapid transmenopausal bone loss observed in late peri andearly posr tmenopausal women. We will study the effects of 18 months of prune consumption in women recruited during the late peri and early postmenopausal stage, allowing a high probability for data collection spanning the transmenopausal period of heightened bone loss i.e., 12 months before the final menstrual period (FMP) and the two years following the FMP. We will also examine the physiological mechanisms underlying the bone trophic effects of prune consumption to seek evidence on how prunes work. If successful, prunes will be demonstrated to be a powerful strategy to attenuate and delay the rapid decline in BMD and decrements in microarchitecture that eventually lead to osteoporosis and heightened risk for fracture.Specific Objective 1: A Focus on Clinical Outcomes: To evaluate the effectiveness of prunes as a dietary supplement to attenuate the rapid bone loss during the transmenopausal period, we will compare the effects of 18 months of daily dietary consumption of 50 g of prunes (50g-P) versus ano-prune (No-P) control group on the primary outcomes that include BMD, bone geometry, and estimated bone strength.Specific Objective 2: A Focus on Mechanistic Outcomes: To evaluate the physiological mechanisms underlying the effects of prunes to attenuate bone loss during the transmenopausal period of rapid bone loss, we will evaluate the effects of 18 months of daily dietary consumption of 50g of prunes/day versus a no-prune control group on: 1) markers of bone metabolism (Trap-5, CTx), 2) markers of inflammation (the inflammatory response of ex vivo cultured PBMCs), and 3) gut permeability and the gut microbiome.A critical gap in osteoporosis prevention. A critical gap in osteoporosis prevention that is not addressed in conventional medicine is the major problem of perimenopausal bone loss that sets women up for osteoporosis. There are no known strategies in place to prevent bone loss during this period even though bone loss is greater than at any other period in a woman's life [8, 16]. This time, referred to as transmenopause, is specifically defined as the 12 months before the FMP and the two years following the FMP [8]. Targeting bone loss during the transmenopausal period is opportunistic since bone loss is at its greatest during this time with women losing as much as 6-7% of bone at the lumbar spine and hip, respectively [8, 16]. We have previously demonstrated that consumption of 6 prunes per day (approximately 50 g) for 12 months preserved hip BMD, cortical volumetric density, and estimated bone strength in women who were, on average, 12 years postmenopausal [17, 18]. Mechanistically, we also demonstrated dietary supplementation with 50-100g of prunes for 12 months reduced proinflammatory cytokine secretion from peripheral blood mononuclear cells (PBMCs) and suppressed the circulating levels of activated monocytes, findings that were associated with enriched gut bacterial taxa such as Lachnospiraceae [1, 19, 20]. These enriched gut bacterial taxa may play a role in producing anti-inflammatory short-chain fatty acids(SCFAs) and likely demonstrate a plausible mechanism for how prunes mediate their health effects, at least in postmenopausal women [1, 17, 19-21]. Given our favorable effects of maintaining bone health in postmenopausal women [17, 18], the goal of the proposed study is to test the effects of prunes in a younger cohort, i.e., mid-life women who are about to experience the most detrimental period of bone loss, the transmenopause [6-8]. Hence, our long-term goal is to test the novel and innovative hypothesis that prune consumption for 18 months during the 3-year transmenopausal period attenuates the dramatic rate of bone loss (slope) in late peri and early postmenopause during this window of heightened physiological vulnerability, favorably positioning women to enter their postmenopause with stronger bones. Prunes are a functional food that is both affordable and accessible, potentially obviating the reliance on poorly adhered-to pharmaceutical drugs for the treatment of osteoporosis [22]. Specifically, well-known anti-resorptive drugs are associated with osteonecrosis of the jaw, atypical hip fractures, and poor compliance rates [22, 23]. As such, our strategy provides a healthy and attractive alternative to pharmaceutical drugs that empowers women to manage their health, i.e., utilize a behavioral nutritional intervention [24] that has a demonstrated high compliance of over 90% [17].References available in full grant documents