The Pathophysiology of Osteoporosis after Spinal Cord Injury

Abstract

Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest neuronal impairment and disability may lead to an upregulation of receptor activator of nuclear factor-κB ligand (RANKL), which promotes bone resorption. Disruption of Wnt signaling and dysregulation of RANKL may also contribute to the pathogenesis of SCI-related osteoporosis. Estrogenic effects may protect bones from resorption by decreasing the upregulation of RANKL. This review will discuss the current proposed physiological and cellular mechanisms explaining osteoporosis associated with SCI. In addition, we will discuss emerging pharmacological and physiological treatment strategies, including the promising effects of estrogen on cellular protection.

Implications of enolase in the RANKL-mediated osteoclast activity following spinal cord injury

“…The pathophysiology of SCI has two phases, a primary phase and a secondary phase. Primary injury involves mechanical trauma, such as compression, laceration, and contusion, and vascular injury to the spinal cord ( Alizadeh et al ., 2019 ; Cox et al ., 2015 ; Hachem et al ., 2017 ; Shams et al ., 2021 ). Cellular damage at the lesion site is considered immediate and irreversible.…”

“…In contrast, secondary trauma describes a cascade of molecular events occurring days to weeks following injury, consisting of neuroinflammation, cell death, and tissue degeneration ( Hachem et al ., 2017 ). SCI-associated inflammation influences the development of chronic ischemic hypoxia, upregulation of Calpain proteases, activation of inflammatory signaling proteins, degeneration of the blood brain barrier, and production of reactive oxygen species ( Cox et al ., 2015 ; Shams et al ., 2021 ). Therefore, the magnitude of the secondary phase of SCI drives the extent of chronic morbidity in individuals with SCI ( Cox et al ., 2015 ; Hachem et al ., 2017 ; Shams et al ., 2021 ).…”

“…Individuals with SCI are likely to experience paralysis-related complications, such as osteoporosis, which can increase their risk of forming fractures and further the reduction of their quality of life ( Hachem et al ., 2017 ; Haider et al ., 2018 ; Shams et al ., 2021 ). Several multidisciplinary mechanisms have been proposed in the literature for their role in bone loss following SCI ( Invernizzi et al ., 2020a ).…”

“…Several multidisciplinary mechanisms have been proposed in the literature for their role in bone loss following SCI ( Invernizzi et al ., 2020a ). Perturbations in the Wnt pathway have been implicated in bone loss ( Shams et al ., 2021 ; Zhao et al ., 2018 ). The Wnt pathway inhibitor, sclerostin, is upregulated following SCI, significantly compromising bone mineral density, bone strength, and bone architecture in rodent models ( Zhao et al ., 2018 ).…”

“…An additional factor in bone loss is mechanical unloading, such as with SCI-induced paralysis, as it has been strongly implicated in the upregulation of sclerostin, as well as the downregulation of periostin, a protein promoting osteoblast activity ( Invernizzi et al ., 2020a ; Zhao et al ., 2018 ). Mechanical unloading may also upregulate osteoblast secretion of RANKL, contributing to increased bone resorption ( Invernizzi et al ., 2020a ; Shams et al ., 2021 ). In SCI, mechanical unloading may contribute to muscle atrophy, having crucial crosstalk with skeletal bone tissue; both smooth muscle cells and osteoblasts secrete inflammatory cytokines and chemokines, such as interleukin-6 (IL-6), during physical inactivity ( Invernizzi et al ., 2020a ; Invernizzi et al ., 2020b ).…”