A vast literature supports the sensitivity of bone to mechanical loading. When mechanical loading is acutely diminished, as occurs with paralysis or other forms of disuse, bone mass is rapidly degraded.¹ Alternatively, bone is also capable of substantial augmentation following long term exercise.² In combination, these observations suggest that mechanical loading of the skeleton is essential for maintenance of bone homoeostasis and holds potential to serve as a substantial anabolic stimulus. Given the extremely debilitating nature of bone loss pathologies and nascent development stage of anabolic interventions capable of enhancing skeletal mass and morphology at both trabecular and cortical sites, examination of how mechanical loading induces bone formation continues to be an area of substantial study.

“…high magnitude loading is not practical for those seniors acutely in need of bone augmentation”

The most efficacious exercise interventions have exposed young developing skeletons to dynamic impact loads such as those induced by jumping.³ The success of such a regimen stems, in part, from the enhanced ability of the developing skeleton to respond to mechanical stimuli compared with an aged skeleton⁴ and, we would argue, the intermittent nature of activities such as jumping. However, although impact exercise interventions may serve to augment peak skeletal strength and thereby serve as a potential prophylaxis for future osteopenias, high magnitude loading is not practical for those seniors acutely in need of bone augmentation. Exercise that is accessible for this population, such as the relatively mild skeletal loading that might be generated by walking or resistance exercise, is not perceived as a stimulus for bone formation.⁵

It is quite likely that a primary contributor to the poor efficacy of exercise interventions in adult and elderly populations has been the incomplete elucidation of specific bone mechanotransduction pathways. In vivo studies of bone adaptation have clearly confirmed that bone is responsive to a variety of specific aspects of mechanical loading such as magnitude and serial bouts of activity.^6,7 Although the benefit of increased loading or activity eventually plateaus, few would argue that the greater the stimulus, the bigger the response of the tissue. Substantial progress has been made in studying the molecular events underlying this pathway, including identification of numerous second messengers, transcription factors, and signal transduction genes, the regulation of which is rapidly altered in various bone cells by mechanical stimuli. However, mechanotransduction within bone remains a largely unresolved area of research.

“…rest insertion serves to reduce the amount and magnitude of mechanical loading required for an intervention to be perceived as stimulatory, even in the aged skeleton”

Our recent efforts in this area have focused on developing strategies to “trick” bone into perceiving that mild loading activities, such as walking, are stimulatory for bone accretion. If successful, such an approach could greatly broaden the use of exercise to build bone mass. In a recent series of in vivo studies, our group (and others) have observed that the insertion of a rest interval between each loading event greatly amplifies the response of bone to loading. This strategy is capable of transforming a brief (100 second) low magnitude regimen that is normally ignored by bone into one that is potently osteogenic. As well, it appears that rest insertion serves to reduce the amount and magnitude of mechanical loading required for an intervention to be perceived as stimulatory, even in the aged skeleton.^8,9,10

The conundrum posed by the effectiveness of rest insertion lies with its contradiction of the “bigger the stimulus, the bigger the response” principle. The potential mechanisms underlying the effectiveness of rest insertion are numerous and may range from simple amplification of standard pathways to activation of alternative signalling pathways. Given the difficulty associated with defining specific biochemical mechanotransduction pathways in vivo, we have begun to explore this question from a different perspective, using approaches of complex adaptive system biology to identify particular aspects of cellular activation that may explain the effectiveness of rest inserted loading.¹¹ Complex adaptive (biological) systems are characterised by internal heterogeneity, hierarchical structure, non-linear interactions, and high degrees of connectivity within and between parts of the system. Approaches used to analyse such systems are typically inductive and are premised on the observation that local interactions (such as generation and/or perception of signalling molecules by adjacent osteocytes) are capable of inducing emergent system behaviours (such as osteoblast activity days or weeks after the loading event).

In this context, we have examined how rest inserted stimuli may be perceived by osteocytes by an agent based modelling technique that is uniquely suited to studying counterintuitive and emergent phenomena. The model predicted that inserting a rest interval between load cycles enhances and sustains signalling activity within osteocytic networks. This augmented signalling arose by a combination of more efficiently exploiting the dynamics of second messenger generation and depletion and by augmenting intercellular communication within the osteocyte network. Thus the model suggests that the osteogenic potency of rest inserted stimuli emerges from real time activity induced within the cellular syncytium of the bone during the brief time—that is, seconds—that the skeleton is subjected to loading. The agent based modelling approach also holds potential for expansion to examine transduction of specific signalling molecules—for example, Ca²⁺ or ATP—or enhanced diffusion of these factors as might be achieved by rest inserted loading. Pending further studies and experimental validation, it appears that biological mechanisms of rest insertion may lie at the level of altering how osteocytes behave within the context of their local cellular neighbourhood.

The specific signalling pathways underlying the effectiveness of rest insertion may prove elusive. However, it is our belief that this strategy may yield positive clinical results without exact knowledge of its mechanism. In this context, our complexity based approach may provide a tool to optimise rest inserted loading waveforms and to design strategies that compensate for potential variations associated with factors such as age or genetic background. With future optimisation, rest insertion holds the potential to enable more bone accretion with less exercise compared with current repetitive loading strategies. Whereas cyclic aerobic exercise undoubtedly confers numerous physiological and psychological benefits beyond the skeleton, a rest inserted exercise regimen, in our view, holds greatly enhanced potential for utilisation in a couch potato era of substantially diminished physical fitness.