A Semi-Empirical Cell Dynamics Model for Bone Turnover Under External Stimulus

Abstract

The normal periodic turnover of bone is referred to as remodeling. In remodeling, old or damaged bone is removed during a ‘resorption’ phase and new bone is formed in its place during a ‘formation’ phase in a sequence of events known as coupling. Resorption is preceded by an ‘activation’ phase in which the signal to remodel is initiated and transmitted. Remodeling is known to involve the interaction of external stimuli, bone cells, calcium and phosphate ions, and several proteins, hormones, molecules, and factors. In this study, a semi-empirical cell dynamics model for bone remodeling under external stimulus that accounts for the interaction between bone mass, bone fluid calcium, bone calcium, and all three major bone cell types, is presented. The model is formulated to mimic biological coupling by solving separately and sequentially systems of ODEs for the activation, resorption, and formation phases of bone remodeling. The charateristic time for resorption (20 days) and the amount of resorption (∼0.5%) are fixed for all simulations, but the formation time at turnover is an output of the model. The model was used to investigate the effects of different types of strain stimuli on bone turnover under bone fluid calcium balance and imbalance conditions. For bone fluid calcium balance, the model predicts complete turnover after 130 days of formation under constant 1000 microstrain stimulus; after 47 days of formation under constant 2000 microstrain stimulus; after 173 days of formation under strain-free conditions, and after 80 days of formation under monotonic increasing strain stimulus from 1000 to 2000 microstrain. For bone fluid calcium imbalance, the model predicts that complete turnover occurs after 261 days of formation under constant 1000 microstrain stimulus and that turnover never occurs under strain-free conditions. These predictions were not impacted by mean dynamic input strain stimuli of 1000 and 2000 microstrain at 1 Hz and 1000 microstrain amplitude. The formation phase of remodeling lasts longer than the resorption phase, increased strain stimulus accelerates bone turnover, while absence of strain significantly delays or prevents it, and formation time for turnover under monotonic increasing strain conditions is intermediate to those for constant strain stimuli at the minimum and maximum monotonic strain levels. These results are consistent with the biology, and with Frost’s mechanostat theory.