EVOLUTION: Of Mice . . .

The observed fit of bone mass to a healthy animal's typical mechanical usage indicates some mechanism or mechanisms monitor that usage and control the three longitudinal growth, bone modeling, and BMU-based remodeling activities that directly determine bone mass. That mechanism could be named a mechanostat. Accumulated evidence suggests it includes the bone itself, plus mechanisms that transform its mechanical usage into appropriate signals, plus other mechanisms that detect those signals and then direct the above three biologic activities. In vivo studies have shown that bone strains in or above the 1500-3000 microstrain range cause bone modelling to increase cortical bone mass, while strains below the 100-300 microstrain range release BMU-based remodeling which then removes existing cortical-endosteal and trabecular bone. That arrangement provides a dual system in which bone modeling would adapt bone mass to gross overloading, while BMU-based remodeling would adapt bone mass to gross underloading, and the above strain ranges would be the approximate "setpoints" of those responses. The anatomical distribution of those mechanical usage effects are well known. If circulating agents or disease changed the effective setpoints of those responses their bone mass effects should copy the anatomical distribution of the mechanical usage effects. That seems to be the case for many agents and diseases, and several examples are discussed, including postmenopausal osteoporosis, fluoride effects, bone loss in orbit, and osteogenesis imperfecta. The mechanostat proposal is a seminal idea which fits diverse evidence but it requires critique and experimental study.

Bone “mass” and the “mechanostat”: A proposal

50 Years of Image Analysis

Basic biomechanical measurements of bone: a tutorial.

Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.

WNT signaling in bone homeostasis and disease: from human mutations to treatments

Rosette strain gauges were attached to the midshaft of the radius and tibia of two horses and two dogs, which ran on a treadmill through their entire range of speed and gait. The relative magnitudes of the principal strains on the opposite cortices of each bone remained constant through the stance phase of the stride, and their orientation varied by a maximum of only 14 degrees through the entire speed range. The maximum strain rate increased linearly with speed, but the peak strain magnitude was also dependent upon the gait used, increasing incrementally by up to 59% at the transition from walk to trot, and dropping by 42% from a trot to a canter. Force transducers attached to the shoes of one horse indicated similar changes in ground load. The peak strains induced during vigorous activity are remarkably uniform in a wide range of animals. This suggests that the skeleton is scaled to provide constant safety margins between peak functional strains and those at which yield and ultimate failure occur.

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Limb mechanics as a function of speed and gait: a study of functional strains in the radius and tibia of horse and dog

Mechanically adaptive bone remodelling.

The influence of strain rate on adaptive bone remodelling

Dynamic strain similarity in vertebrates; an alternative to allometric limb bone scaling.

Mechanical function has always been acknowledged to have a significant, continuing but hitherto unquantified influence on bone remodeling. The structural objective of this relationship is presumably to ensure that, at each location throughout the skeleton, there is sufficient bone tissue, appropriately placed, to withstand functional load-bearing without damage. The architectural modifications necessary to achieve and maintain this structural competence are made by the coordinated remodeling activity of populations of osteoblasts and osteoclasts. The specific structure-function objectives at each location remain undefined, as are the mechanisms by which tissue loading is transduced into cellular control. The remodeling responses following a variety of experimental alterations in bones' strain environment are presented. Their significance to the process of remodeling control is discussed, and a scheme for the interaction of mechanical and hormonal influences proposed.

Lance E. Lanyon

Papers

Limb mechanics as a function of speed and gait: a study of functional strains in the radius and tibia of horse and dog

Mechanically adaptive bone remodelling.

The influence of strain rate on adaptive bone remodelling

Dynamic strain similarity in vertebrates; an alternative to allometric limb bone scaling.

Functional strain as a determinant for bone remodeling