Asti Raamann

Background: Spinal cord injury (SCI) affects 54 per one million individuals in the United States each year¹. In addition to loss of motor, sensory and physiological functions, one prominent, yet overlooked, complication of SCI is bone loss. People with SCI lose approximately 50% of trabecular bone below the level of injury within two years, and about half of all SCI patients experience a bone fracture, often resulting in secondary effects such as sepsis, non-union, and decreased rehabilitation potential^2,3. Currently, treatment for SCI-induced bone loss includes weight-bearing therapies, but it was recently discovered that bone loss is not solely due to disuse⁴. Alternate treatments include zoledronic acid, a bisphosphonate that promotes osteoclast apoptosis. While bisphosphonates do decrease bone loss at the hip they do not prevent fracture at the knee joint– the most common fracture site after SCI⁵. SCI is characterized by chronic inflammation⁶, and chronic inflammation has been linked to osteoclast proliferation via TNF-ɑ receptors and the RANKL pathway^7,8. Since TNF-ɑ inhibits differentiation of osteoblasts and increases differentiation of osteoclasts, a novel two-pronged approach to ceasing bone loss can be explored. Targeting the pro-inflammatory RANKL pathway could be explored to inhibit SCI-induced bone loss.

Objective: This review explores the mechanisms underlying bone loss following SCI and proposes alternate treatment targeting the TNF-ɑ signaling pathway.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “spinal cord injury”, “bone loss”, “RANKL pathway”.

Results: Studies consistently show up to a 2.5-fold increase in osteoclast surface, 37% lower cancellous bone formation rate, and decreased osteoid surface in the proximal tibia following SCI⁶. Although SCI-induced bone loss was previously thought to be due to disuse, recent studies indicate that this is not the only factor driving bone loss. Indeed, in rat SCI models that spontaneously recover weight-bearing and locomotor function, bone loss still occurs⁴. The literature indicates that current treatments, including zoledronic acid, are also not effective at sites with high fracture risk: femur and tibial bone mineral content continued to decline following two doses of zoledronic acid⁵. Thus, it is imperative to investigate alternate mechanisms of bone loss. Studies showed significantly elevated pro-inflammatory markers TNF-ɑ, IL-6, and IL-10 in osteocytes following SCI^6,9. TNF-ɑ, specifically, acts on osteoblasts to inhibit their differentiation and to stimulate RANKL expression, which in turn stimulates osteoclast differentiation⁸. TNF-ɑ also acts on osteoclasts directly via RANKL expression⁸. RANKL induces the transcription factor NF-κB to promote expression of genes c-Fos and EEIG1⁷, which both stimulate osteoclastogenesis. Targeting expression of TNF-ɑ could be a promising method for reducing SCI-induced bone loss. Following injury, enolase is known to present antigens at the cell surface and trigger the circulation of pro-inflammatory markers¹⁰. Experimentation with ENOblock, an enolase inhibitor, has demonstrated success in decreasing levels of these markers at the level of injury¹⁰. Studies using ENOblock to reduce bone loss after SCI are warranted.

Conclusions: There is a chronic state of inflammation after SCI that may contribute to the bone loss and increased risk of fracture associated with injury. Enolase inhibition, which shows promise in decreasing levels of pro-inflammatory markers such as TNF-ɑ, could prevent bone loss following SCI.

Works Cited:

1.  Bennett J. Spinal Cord Injuries. StatPearls [Internet]. May 11, 2022. Accessed February 11, 2024. https://www.ncbi.nlm.nih.gov/books/NBK560721/.
2. Spinal Cord Injury Facts and figures at a glance – NSCISC. National Spinal Cord Injury Statistical Center. 2019. Accessed February 11, 2024. https://www.nscisc.uab.edu/Public/Facts%20and%20Figures%202019%20-%20Final.pdf
3. Varacallo M. Osteoporosis in Spinal Cord Injuries. StatPearls [Internet]. August 28, 2023. Accessed February 11, 2024. https://www.ncbi.nlm.nih.gov/books/NBK526109/.
4. Metzger CE, Rau J, Stefanov A, et al. Inflammaging and bone loss in a rat model of spinal cord injury. Journal of Neurotrauma. 2023;40(9-10):901-917. doi:10.1089/neu.2022.0342
5. Edwards WB, Haider IT, Simonian N, Barroso J, Schnitzer TJ. Durability and delayed treatment effects of zoledronic acid on bone loss after spinal cord injury: A randomized, controlled trial. Journal of Bone and Mineral Research. 2021;36(11):2127-2138. doi:10.1002/jbmr.4416
6. Metzger CE, Gong S, Aceves M, Bloomfield SA, Hook MA. Osteocytes reflect a pro-inflammatory state following spinal cord injury in a rodent model. Bone. 2019;120:465-475. doi:10.1016/j.bone.2018.12.007
7. Park JH, Lee NK, Lee SY. Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation. Mol Cells. 2017;40(10):706-713. doi:10.14348/molcells.2017.0225
8. Kitaura H, Marahleh A, Ohori F, Noguchi T, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Role of the Interaction of Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors 1 and 2 in Bone-Related Cells. International Journal of Molecular Sciences. 2022; 23(3):1481. https://doi.org/10.3390/ijms23031481
9. Thakkar P, Prakash NB, Tharion G, et al. Evaluating bone loss with bone turnover markers following acute spinal cord injury. Asian Spine Journal. 2020;14(1):97-105. doi:10.31616/asj.2019.0004
10. Polcyn R, Capone M, Matzelle D, et al. Enolase inhibition alters metabolic hormones and inflammatory factors to promote neroprotection in spinal cord injury. Neurochemistry International. 2020;139:104788. doi:10.1016/j.neuint.2020.104788