Bone adaptation: Roles of fluid flow and pore pressure

Abstract

Bone loss is a serious health problem associated with old age and bone/muscle disuse. Classic examples such as elderlies, astronauts, patients having spinal cord injuries, etc., show the symptoms of bone loss and are vulnerable to fracture risk. Several factors are responsible for bone resorption, such as loss of mechanical environment, hormonal deficiency, genetics, and nutrition. In the last few decades, mechanical loading and pharmacological agents proved themselves as a solution as they reverse this degenerative process, encourage new bone formation, and reduce resorption. However, long-term use of these pharmacological agents is expensive and has side effects such as pain, nausea, etc. Therefore, mechanical loading holds promise as a less costly and nonpharmacological means to mitigate bone loss. In vivo and in silico studies have shown that load-induced fluid flow in lacunae canalicular network (LCN) inhibits bone loss and promotes new bone formation, suggesting that load-induced interstitial fluid flow (IFF) in LCN may be a primary stimulus as it exerts shear and drags forces on osteocytes. Accordingly, most of the current mathematical models consider fluid flow as a stimulus for osteogenesis. However, these models fail to predict new bone formation simultaneously at both the periosteal and endocortical surfaces. To the best of our knowledge, no unifying principle relates new bone formation (simultaneously at both surfaces) with its mechanical environment. Besides IFF, it has also been shown that pore pressure generated under physiological loading conditions is adequate to enable osteocytes to respond. Despite the importance of IFF and Pore pressure, their exact roles have not yet been established. In order to fill the research gap, this thesis investigates the role of fluid flow and pore pressure on site-specific new bone formation induced by exogenous mechanical loading. A novel derivation of mineral apposition rate (MAR) in terms of dissipation energy density has been introduced, hypothesizing that the Mineral Apposition Rate (MAR) is proportional to the square root of the dissipation energy density minus its reference value. Dissipation energy density is selected as a stimulus due to its capacity to incorporate both fluid flow and pore pressure. Computational implementation of the mathematical model has been carried out through a poroelastic finite element analysis, where the bone is assumed to be porous and filled with fluid, with a boundary condition that the periosteum is impermeable to the fluid and the endosteal surface maintains a reference zero pressure. The fluid velocity and pore pressure estimated from the above analysis are used to calculate the dissipation energy density. This new mathematical model tested the role of fluid flow and pore pressure individually and in combination to predict cortical bone adaptation. The results indicate that fluid flow or pore pressure alone as a stimulus cannot predict osteogenesis at both cortical surfaces. In contrast, in combination, fluid flow and pore pressure closely fit site-specific new bone formation on both surfaces. It affirms that more than one mechanical stimulus is required to predict load-induced osteogenesis. The model has also been tested for another in vivo loading protocol and has been found precise in predicting new bone distribution. As a bottom line, the resulting model is the first of its kind, as it has been able to correctly predict MAR at both endocortical and periosteal surfaces. This study thus significantly advances the modeling of cortical bone adaptation to exogenous mechanical loading. Based on the findings, an overall bone formation model is also developed, directly measuring the average bone formation rate (BFR) on both cortical surfaces. This model further substantiates the role of fluid flow and pore pressure in bone adaptation.