Background:  Spinal cord injury (SCI) is a medical condition that affects the nerves running through the spinal cord and is often the result of major trauma such as motor vehicle collisions or falls.¹ 54 people per million in the United States with an estimated total ranging from 255,000 to 383,000 people.¹ SCI results in significant bone degeneration following the injury, leading to higher fragility fractures and increased mortality. Bone resorption in SCI has been shown to be caused by neurovascular changes, hormonal changes, and mechanical unloading.² Though difficult to characterize, recent findings suggest that the cellular mechanism of osteoporosis in SCI may be caused by an upregulation of the receptor activator of nuclear factor-κB ligand (RANKL) and the Wnt signaling pathway.³ These findings suggest the RANK/RANKL pathway play an important role in bone loss following SCI.

Objective: In this narrative review, we explored how bone loss occurs following spinal cord injuries through the RANK/RANKL pathway and the potential therapeutics.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using the following keywords: “Spinal cord injury”, “RANKL”, “bone loss”, and “drug therapy”.

Results:  SCI has shown to decrease osteoprotegerin (OPG) expression which promotes RANKL/RANK signaling and peroxisome proliferator-activated receptor-γ (PPARγ) expression which increases RANKL expression.³ The rats with induced SCI had a significant lower expression of osteoblastic genes. The genes COL1A, OSX, and RUNX2 were all significantly lower in SCI rats, resulting in inhibited osteoblast differentiation at several stages.⁴ The SCI group had a significant 273% increase in RANKL-positive area and 112% in the RANKL-positive area on staining, indicating greater bone resorption and osteoclast activity.⁴ Other studies also showed that this pathway could be potentially targeted for therapy. Polydatin (PLD) has been used to help osteogenic differentiation and exhibit anti-osteoporotic activity.⁵ Treatment with PLD in SCI mice models helped to restore bone mineral density, enhanced bone formation, and inhibited bone resorption.⁵ Untreated mice had 40% reduction in OPG mRNA levels and twofold increase in RANKL mRNA expression, while the mice treated with PLD upregulated OPG mRNA and downregulated RANKL mRNA.⁵ Denosumab is an anti-RANKL antibody that binds directly to the RANKL receptor and inhibits the activation of RANK therefore decreasing RANK-mediated osteoclastogenesis.^6,7 In a clinical trial, administration of denosumab in patients with sub-acute SCI maintained areal bone mineral density in the knee.⁷ The clinical trial showed that the placebo group lost a significantly greater areal bone mineral density compared to the patients receiving Denosumab in the hip and  distal femur metaphysis.⁷

Conclusion:  Though the exact reason why bone loss occurs following SCI remains unclear, there is significant evidence that the RANK/RANKL system gets dysregulated in this patient population. Targeting of the RANK/RANKL system has shown great potential as a therapy in SCI and further advancements can help patients improve their quality of life. Denosumab should be considered as a strong candidate for patients suffering from SCI, but longer trials should be conducted to monitor for long term adverse effects and total bone loss over time.

Works Cited:

1. National Spinal Cord Injury Statistical Center, Traumatic Spinal Cord Injury Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, 2023.
2. Abdelrahman S, Ireland A, Winter EM, Purcell M, Coupaud S. Osteoporosis after spinal cord injury: aetiology, effects and therapeutic approaches. J Musculoskelet Neuronal Interact. 2021;21(1):26-50.
3. Shams R, Drasites KP, Zaman V, et al. The Pathophysiology of Osteoporosis after Spinal Cord Injury. Int J Mol Sci. 2021;22(6):3057. Published 2021 Mar 17. doi:10.3390/ijms22063057
4. Butezloff MM, Volpon JB, Ximenez JPB, et al. Gene expression changes are associated with severe bone loss and deficient fracture callus formation in rats with complete spinal cord injury. Spinal Cord. 2020;58(3):365-376. doi:10.1038/s41393-019-0377-y
5. Zhan J, Luo D, Zhao B, et al. Polydatin administration attenuates the severe sublesional bone loss in mice with chronic spinal cord injury. Aging (Albany NY). 2022;14(21):8856-8875. doi:10.18632/aging.204382
6. Ding Y, Cui Y, Yang X, et al. Anti-RANKL monoclonal antibody and bortezomib prevent mechanical unloading-induced bone loss. J Bone Miner Metab. 2021;39(6):974-983. doi:10.1007/s00774-021-01246-x
7. Cirnigliaro CM, La Fountaine MF, Parrott JS, et al. Administration of Denosumab Preserves Bone Mineral Density at the Knee in Persons With Subacute Spinal Cord Injury: Findings From a Randomized Clinical Trial. JBMR Plus. 2020;4(8):e10375. Published 2020 Jun 25. doi:10.1002/jbm4.10375