Spinal cord injury (SCI) is a severe neurological disorder that results from sudden and damaging impact to the spine and vertebrae
[1][2]. SCI is one of the most commonly caused damages in vehicle injuries
[3], but can also be caused by falls, athletic injuries, and various other reasons
[4]. SCI impacts more than 10,000 individuals each year and poses a significant economic burden to the U.S
[5]. SCI can be detrimental and life threatening, and while there are therapeutic modalities being studied, more research on how to mitigate the short- and long-term effects of SCI is still needed. The immediate impacts of SCI can vary and depend largely on the specific location and magnitude of the injury
[1][6]. In general, the higher up the level of injury is to the spinal cord, the more severe the symptoms. Injuries to the spinal cord of any magnitude and location can have both localized and global effects on bone composition. The local effects include paralysis, reduced function in the lower body, and bone loss, most commonly in the femurs, tibias, fibulas, and pelvic bones. The global effects of SCI (i.e., neurogenic bone loss) include changes in neural signaling over time, which can lead to a disruption in bone remodeling throughout the body, not just in regions directly impacted by the SCI. The global effects of SCI may also include disruptions to bone vascularity, as there is a synergistic relationship between the skeletal and vascular systems. A decrease in bone vascularity and reduced neoangiogenesis can limit the healing capacity and progress of SCI rehabilitation modalities, and thus limit bone remodeling and repair
[7]. People with a SCI are two to five times more likely to die prematurely than people without an SCI, and this carries substantial individual and societal costs. Short-term impacts often include gliosis, axonal damage, neuronal death, immobilization, and a loss of sensory and motor function, while long-term impacts include organ dysfunction, sarcopenia, osteopenia, bone fractures, and osteoporosis
[1][4][8].
2. Pathophysiology of Bone Loss after SCI
Individuals with complete paralysis after SCI show the most extensive bone loss and fracture risk
[25][26]. Understanding the mechanisms that lead to bone loss and osteoporosis after SCI is important to determining how to slow bone loss after SCI. Common causes of bone loss after severe SCI are immobility and de-loading, which result in increased bone resorption and a decrease in osteoblast activity
[4][27]. When one is immobile due to an injury, less stress is placed on the bones, leading to a direct response from other systems in the body, including the neurogenic and musculoskeletal systems
[27]. Immobility has a direct effect on the musculoskeletal system, since it causes an increase in bone resorption and a decrease in osteoblast activity, resulting in osteopenia
[4][27]. However, bone loss following SCI is believed to be distinct, as compared to the response to other disuse conditions in terms of both severity and mechanism. Although
ourthe focus is SCI, other factors secondary to SCI may also promote bone loss, including systemic hormonal changes, altered bone innervation, and impaired bone perfusion
[26][28]. In an SCI study conducted on rats, significant bone loss was observed during a bone compartment analysis on the SCI animals compared to controls
[11][29]. Overall, decreases in bone mineral content, trabecular structure, and bone mineral density were observed in all the SCI groups.
The next systems that immobilization and bone loss impact are the CNS, peripheral nervous system (PNS), and endocrine system. Bone cells have many nerve endings close to them, which greatly impact the CNS and PNS. Bone cells also connect the skeleton to the endocrine system through various receptors and neuromediators
[27]. Skeletal loss may also promote sarcopenia and endocrine system dysfunction via multiple receptors and neuromediators, thus influencing the adipose tissue production of leptin and anorexigenics, which both affect bone remodeling
[27][30]. Moreover, immobilization impacts skeletal vascularization, which is required for bone remodeling and osteoblast function. The resulting vasoconstriction further contributes to the muscular, endocrine, and nervous system impairments associated with osteoporosis in SCI patients.
The vascular system is a necessary contributor to osteogenesis after SCI. Neo-angiogenesis (i.e., the formation of new blood vessels) plays a crucial role in bone development after SCI, because it ensures that bone tissues are obtaining the necessary blood and oxygen supply to stimulate bone formation, maintenance, and repair
[7]. Following SCI, individuals often experience disruptions to the circulatory system from mechanical trauma. Ischemia, hypoxia, and localized edema are potential secondary effects of SCI impacting the vascular system, thus impeding healing and rehabilitation
[31]. The secondary effects of SCI on the vascular network not only potentially cause secondary injury and can further deteriorate bone and spinal cord tissue, but a reduced vascularity can also mitigate healing from SCI treatment
[7][31]. Various SCI treatments, including cell transplantation, are ineffective if the local blood vessels are damaged, leading to a lack of oxygen and nutrients that the transplanted cells need for survival
[31]. Pericytes and endothelial cells are important structures of the vascular system that play essential roles in angiogenesis; however, they cannot sustain and mediate angiogenesis to osteogenesis when there is damage to the blood vessels in the affected area
[7][31]. Physical rehabilitation and therapeutic strategies, such as surgical anastomosis and exogenous pericyte cell transplantation, are available to help to stimulate angiogenesis after SCI
[7]. Research is still limited on the effectiveness of therapy and rehabilitation for stimulating angiogenesis after SCI.
3. Therapeutic Strategies for Neurogenic Bone Loss after SCI
3.1. Pharmacological Therapy
Pharmacological therapies for the bone loss in SCI individuals have been relatively ineffective. While vitamin D supplementation is commonly used to restore the vitamin D levels in SCI individuals with a vitamin D deficiency, it has not been effective in preventing and restoring bone loss
[32]. Thus, multiple pharmacological strategies may provide benefits for neurogenic bone loss after SCI. For example, ellagic acid (EA) has been found to bind to RANKL and downregulate osteoclast activity, although this endogenous compound may produce negative side effects at elevated concentrations
[33][34][35]. Bisphosphonates and Denosumab have also been evaluated for their prevention of the loss of bone mass after SCI (
Figure 1). Bisphosphonates act to slow bone loss by inhibiting bone resorption; these include Etidronate, Clodronate, Pamidronate, Tiludronate, and Alendronate
[36][37][38]. Bisphosphonates used in SCI patients have been shown to reduce the risk of hip fractures (but not knee fractures)
[29][39].
Figure 1. Rehabilitation Methods for Neurogenic Bone Loss After SCI.
Despite some success, the effects of bisphosphonates have been inconsistent. Clodronate, Etidronate, and Tiludronate have been shown to yield increased bone mass in less than one year post injury (
Figure 1), whereas Alendronate improved bone mass in more than one year after injury
[36]. However, Pamidronate was not shown to improve bone mass in this study. In addition, the prolonged use of bisphosphonate therapy may produce adverse effects such as osteonecrosis of the jaw; thus, judicial administration is advised
[40]. These therapies are currently available in oral or intravenous administrations, and single annualendroal bisphosphonate injections may be available for SCI patients in the future
[29][40][41]. In a recent larger clinical trial on patients with chronic SCI, Teriparatide treatment was used, which resulted in a significant increase in spine BMD at 1 year and further improvements in the hip at 2 years
[42][43]. Furthermore, Denosumab, a monoclonal antibody to RANKL, is FDA approved for osteoporosis treatment
[44][45]. Denosumab prevents bone loss in SCI patients via the inhibition of osteoclast activity via the RANKL pathway, however, it must be frequently administered
[39][46][47][48]. Denosumab thus reduces bone resorption and increases bone mineral density, reducing the risk of fractures.
3.2. Nonpharmacological Therapy
Pharmacological therapies to date are limited, as they do not provide a significant restoration of damaged spinal cord parenchyma. Therefore, non-pharmacological approaches, such as mesenchymal stem cell (MSC) therapy, physiotherapy, immunotherapy, injectable hydrogels, and stem cell secretome therapy, are under consideration
[49][50]. MSCs from the bone marrow, umbilical cord, and/or adipose tissue may reduce inflammation and provide neuroprotective effects to prevent further injury to the spinal cord near the impact site. Injectable hydrogels, which facilitate MSC targeting, are also being studied
[51].
These therapies, in conjunction with weight-bearing rehabilitation, may be increasingly employed to decrease osteopenia in patients with SCI
[52][53]. Following SCI, a primary catalyst behind bone loss is the decrease in mechanical loading. When individuals with SCI cease weight-bearing activities, they face a heightened susceptibility to rapid bone resorption and osteocyte apoptosis, frequently leading to the development of osteoporosis. Engaging in any form of mechanical loading on the skeletal system, including compression, tension, torsion, or bending, will uphold bone density and promote bone mass recovery
[54]. Therapies aimed at this axial loading encompass activities such as walking, jogging, and jumping. Rehabilitations that stimulate mechanical loading are practical, non-invasive, and economical methods for stimulating bone regeneration
[55]. Rehabilitation improves mechanical loading by exposing tissues to a range of strains and forces, prompting osteocytes to sense stress and begin to stimulate regeneration
[56]. Reciprocally, the subjection of mechanical loading on tissues from rehabilitation has been shown to be an effective therapy for tissue regeneration, which ultimately improves the bone’s capacity for mechanical loading
[55]. Rehabilitation also enhances mechanical loading by modifying and improving vascularization, thereby facilitating bone growth. Therapies with an increased musculoskeletal load have proven effective; however, this approach is limited in patients who are wheelchair-bound after SCI. Stand-up wheelchairs, standing frames, and suspended treadmills can provide useful alternatives
[11][57][58]. Physical activity, which inherently stimulates the axial loading of the tibia, femur, and axial skeleton, may also promote bone density after SCI by improving bone vascularization and osteoblast activity
[4][58].
Static loading and prone position muscle stimulation appear to be less effective techniques for the attenuation of bone loss after SCI
[4][59]. Thus, functional electrical stimulation (FES) rowing following SCI has been evaluated. FES rowing employs cyclical exercise patterns coupled with electrical stimulation to simulate the functional motor patterns otherwise impaired by SCI. Rowing allows for paraparetic SCI patients to exercise in a sitting position (in some cases with a cycle ergometer), coordinating their upper body movements with the electrical stimulation of the lower body muscle groups to recreate the effects of full-body exercise
[36][59][60]. In one trial, the bone loss in the distal femur and tibia appeared to be reduced in the majority of participants after 30 sessions; however, other results have suggested that bone loss is ameliorated with muscle electrical stimulation alone. Non-mechanical load-bearing exercises such as swimming and cycling are weaker therapies in terms of reducing bone loss; however, they have still been shown to be effective at maintaining muscle mass, which can indirectly reduce fracture risk. Further studies are therefore needed to determine how these therapies can be best implemented for SCI individuals who are wheelchair-bound. It is important to note that the extent of improvement in mechanical loading after SCI is highly dependent on individual aspects such as the severity of the injury. To yield the best results, rehabilitation should be started early, be consistent, and be tailored to individual needs and goals.