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.

Keywords: Estrogen (E2); Osteoprotegerin (OPG); RANKL; Wnt; bone loss; neurodegeneration.

Figure 1

Typical bone remodeling vs. bone remodeling in individuals with spinal cord injury (SCI). (a) In individuals without SCI, bone remodeling is typically a balanced process. Transcription factors nuclear factor-κB (NF-kB), c-Fos, and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) secreted by osteoblasts are activated, stimulating the maturation of mononucleated osteoclast progenitors. Mature osteoclasts secrete cathepsin K and hydrochloric acid (HCl) to dissolve the bone matrix, with resulting calcium resorption. Moreover, Wnt protein can bind to receptors on osteoblasts. Upon activation, osteoblasts form a layer across the surface of the dissolved bone for calcification. When these processes are coupled, bone integrity is preserved. (b) In individuals with SCI, bone remodeling is no longer balanced, resulting in osteoporosis. Receptor activator of nuclear factor-κB (RANK) ligand binds to RANK receptors on osteoclasts, inducing TNF receptor-associated factor 6 (TRAF-6) recruitment and activation of transcription factors c-Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK), alpha serine-threonine protein kinase (Akt) and NF-κB. These factors participate in various cellular signaling pathways to induce osteoclastogenesis. Furthermore, Wnt protein may be unable to bind due to the presence of Wnt-receptor competitive inhibitors (e.g., sclerostin (SOST)), preventing osteoblast activation. Therefore, increased bone resorption occurs without osteoblast-mediated bone construction. Bone integrity is compromised with resulting osteoporosis.

Figure 2

Protective effects of estrogen (E2) against osteoporosis. When there are low levels of E2 in the body, interleukin 2 (IL-2), interleukin 3 (IL-3), and tumor necrosis factor (TNF)-α are upregulated, while TNF-β is downregulated. The concerted effects of these increased levels of cytokines induce downregulation of competitive osteoprotegerin (OPG) and the upregulation of receptor activator of nuclear factor-κB ligand (RANKL). Increased RANKL contributes to osteoclast differentiation, subsequently increasing bone resorption. Inversely, when there are higher levels of E2 in the body, IL-2/IL-3/TNF-α are downregulated, and TNF-β is upregulated-initiating a cascade of increased OPG and decreased RANKL expression. Osteoblast differentiation occurs at an increased pace (preserving bone integrity), particularly in osteoporosis-prevalent conditions, such as SCI. Orange arrows indicate pathway governing osteoblastogenesis, while blue arrows indicate pathway governing osteoclastogenesis.