The bone response to exercise: a translational research program exploring clinical and mechanistic aspects

Abstract

Exercise is an important means to optimize bone accrual and maintenance throughout the lifespan and to manage or treat conditions that cause bone loss or weakening. Additionally, the use of distinct exercise types and intensities provides unique opportunities to investigate the bone response to various metabolic and mechanical signals, thus providing an in vivo model to study bone physiology. Despite the importance of exercise as a model to understand basic bone physiology, and as a strategy to enhance bone health, little is known about the pathways that mediate the bone response to exercise, nor of the factors that moderate this response. Thus, the ability to develop and administer targeted and effective therapeutic exercise programs is limited. The proposed research program sits at the crucial interface between basic and applied science, and addresses important knowledge gaps in this topic area. As recommended by the UK Medical Research Council (along with many other research bodies), the original investigations described herein will be preceded by a statistical meta-analysis of all available data on the bone metabolic response to exercise (Study 1). Onward progression of knowledge in this clinically essential area is impeded by an incomplete understanding of current data, and this is mainly due to large heterogeneity in study design and quality. The proposed rigorously designed meta-analysis will combine high-quality data using multi-level modelling based on Bayesian principles, and will ensure that the proposed research program is grounded in the most up-to-date and highest-quality evidence available. Central to the proposed research program is a clinical RCT (Study 2), which will investigate the independent and combined influences of exercise training and protein supplementation on bone in a group of patients prescribed high-dose glucocorticoid therapy (GCT). This group are highly susceptible to bone loss and fracture, but the potential of exercise to protect bone when delivered as an adjunctive therapy to GCT has never been examined. Within this study, we will investigate important clinical outcomes (including bone mass and micro-architecture, along with physical function). To provide additional scientific rigor, we will also use bone biopsies and bone biomarkers to glean more in-depth mechanistic insight into the clinical results obtained. This clinical trial will be complemented by a number of in vivo laboratory-based mechanistic studies, within which we will examine the bone metabolic response to acidosis (Study 3) and exercise type (Study 4). Additionally, we will examine how important nutritional factors - namely energy availability and protein intake - moderate the bone response to exercise (Study 5).There is a critical need to understand better the specific factors that regulate the bone response to exercise, to ensure that lifestyle intervention interventions and recommendations are effective and fit-for-purpose. Collectively, this ambitious, novel and comprehensive research program will provide unique insights into the complex relationship between exercise and bone, along with the modifiable factors that mediate this response. Importantly, the data attained, in addition to its numerous direct therapeutic and clinical applications, will provide a foundation on which an extensive on-going research program can be built. In line with the objectives of the Young Investigator program, we are confident that the current proposal has all of the ingredients required to develop an innovative and impactful research line and group, that will serve as an internationally recognised centre of excellence for research investigating the bone response to exercise and nutrition, along with the clinical applications of this approach. (AU)