Clinton T. Rubin

CHAPTER 4 – Constraints of Experimental Paradigms Used to Model the Aging Skeleton

This chapter discusses the importance of some of the models employed for studying the aging process to emphasize the interdependence of diverse and distinct entities in determining the etiology of age-related bone disease. One must consider parameters beyond bone density that contribute to bone quality such as turnover, connectivity, organic constituents, ultrastructural integrity, and organization. With an improved understanding of what provides the skeleton with its structural success, one may be able to identify which parameters become dysfunctional in the aging human. The majority of in vivo protocols used to study the aging process in general, and the aging skeleton in particular, focus on Rattus novegicus, the laboratory rat. While the rat may be an effective initial screening tool to identify anabolic agents, the limitations in extrapolating perturbations of bone growth to the slow, progressive degeneration of bone morphology must be accepted.

Interdependence of Genetic and Epigenetic Factors in Determining Bone Strength

Bone is an elegant biologic structure that succeeds at withstanding extremes of functional loading while simultaneously serving as the organism’s principal reservoir of mineral. The strength of the skeleton is realized via a sophisticated structural and ultrastructural organization that has evolved to meet specific functional demands. Bone’s success as a structure cannot be quantified simply by density (Figure 1). Trabecular girth, orientation and connectivity, cell responsiveness to anabolic and catabolic agents, the distribution, organization and competence of the organic constituents, and even the neuromuscular (postural stability, falling reflex) and cardiovascular systems (metabolite distribution) are all critical to the structural success of the skeleton. The multifold functional demands on the skeleton and the need to continually sense and adjust to those demands suggest that a simple genetic template cannot be the sole determinant of skeletal morphology.

Prevention of Osteoporosis by Physical Signals

Stephen Jay Gould’s commentary on Darwinism emphasizes the vital importance of an organism’s ability to adapt effectively to changing signals arising from the environment. Pressure, gravity, waves, temperature, light, electric, and magnetic fields make up an omnipresent physical presence since the beginning of time. It should be no surprise, therefore, that the capacity of biologic systems to adapt to physical signals is a common attribute for essentially all life, including bacteria, yeast, plant, and animal cells, and that the cellular machinery responsible for sensing and responding to mechanical signals evolved during billions of years of exposure to a range of physical challenges. The evolutionary success of any organism has always been based on its ability to accommodate, acclimate, and adapt to changes in its immediate temporal and spatial environment. It should not be difficult to recognize that the primacy of vertebrates through the past 500 million years has been achieved through highly orchestrated adaptation to physical signals. Thus, if physical signals could be harnessed to prevent or reverse the age-, injury-, or disease-related deterioration of the musculoskeletal system, it would diminish dependence on pharmacologic agents prescribed for these goals.