Neuronal LTP has clear analogies to osteogenesis resulting from brief periods of mechanical loading particularly in as much as they are both long-lasting forms of use-dependent potentiation. This prompted the hypothesis that memory formation in bone and brain share a common cellular pathway. Mechanical loading is arguably the most potent environmental influence on the skeleton and promotes new bone formation through modelling and remodelling. In contrast, disuse, immobilisation and weightlessness are associated with bone loss 23242526. Mechanical influences on the skeleton and the adaptive responses of bone cells to recent loading history have been described as the primary functional determinant of skeletal architecture 27. In simple terms, dynamic alteration in bone structure induced by loading serves to improve its structural suitability to subsequent loading events. Bone cells learn from changes in their loading environment so that the activity of cells are precisely orchestrated to control modelling and remodelling and preserve optimum skeletal structure. This protective mechanism of cause and effect acts to prevent skeletal damage that would otherwise result from habitual physical activity. The osteogenic potency of mechanical strain on bone cells is such that single brief periods of loading are able to exert a long-lasting osteogenic response in vivo 28. The temporal nature of this response, transducing mechanical stimuli into an appropriate level of consolidatory bone formation that outlasts the stimulus, necessitates the existence of a form of cellular memory.

Evidence exists for conventional memory formation in bone in which responses to mechanical loading are affected by preceding episodes of loading, at least fulfilling the conceptual requirement for LTP. For instance, it has been demonstrated that mechanical loading is more osteogenic when separated into discrete episodes, compared to an equivalent period of uninterrupted loading. Using a well-characterised model of loading induced bone formation in vivo, several studies have demonstrated that the osteogenic potential of mechanical loading is enhanced in terms of bone formation and biomechanical and structural properties, by separation of loading cycles into discrete episodes with varying degrees of rest between periods of stimulation 293031. In these studies, the order of osteogenic potency was such that 6 periods of 60 cycles > 4 periods of 90 cycles > 360 cycles at once. These data were interpreted as bone cells becoming increasingly less responsive or 'deaf' to prolonged periods of mechanical stimulation, a form of depression or desensitisation to the stimulus. Based on a hypothesis of LTP in bone described here, in contrast to losing responsiveness, bone cells could be considered primed by earlier periods of loading, so that further episodes are increasingly efficacious and subsequent responses potentiated. This would account for the extrapolatory deduction that less total loading cycles should be required to produce the equivalent level of osteogenic response if loading is separated into discrete bouts compared to a single sustained, and less effective period of loading. Moreover, other studies have reported that the osteogenic response of mechanical strain increases with loading frequency 32, which has clear similarities to LTP in central neurones, which is more effectively induced by high frequency stimulation. Lower frequency stimulation on the other hand is associated with short-term potentiation (STP) or long-term depression (LTD). Perhaps most significantly, LTP in bone would also account for the observation that levels of osteogenic stimulus saturate rapidly so that only a few loading cycles are required to achieve the maximum osteogenic effect 33. In support of LTP-like mechanisms mediating the osteogenic response of bone cells, key events involved in LTP are observed in osteoblasts following mechanical stimulation in vitro, including specific and rapid initiation of calcium transients and activation of neuronal CaMKII. Furthermore, CaMKII activity appears to be required for normal osteoblast differentiation, which temporally precedes new bone formation post-loading 3435. In vivo evidence also exists for the involvement of an LTP-like mechanism in loading induced osteogenesis; potent inhibition of AMPA/Kainate receptor activation with DNQX causes a significant decrease in loading induced bone formation in the 4-point bending rat ulnae model 36. This could be interpreted as functional antagonism of potentiated AMPA receptor responses induced by LTP-like mechanotransduction in bone.