Samuel Tran

Background: Spinal cord injury (SCI) leads to rapid deterioration of cortical and cancellous bone below the lesion site, creating significant risk for fractures and limiting rehabilitative options such as weight-bearing exercises and exoskeleton use. ¹ Skeletal deterioration reflects an imbalance between osteoblast and osteoclast function, mainly at the distal femur and proximal tibia. Conventional therapies, including bisphosphonates and denosumab, slow bone loss but fail to restore bone density. ² Furthermore, SCI secondary injury is characterized by neuroinflammation, oxidative stress, and microglial activation, which commonly alter RANKL/OPG signaling, a major pathway in bone metabolism.^3,4,5 Current treatments do not adequately address both the neuroinflammatory and osteogenic aspects of SCI-induced osteoporosis. As a result, emerging biological interventions targeting specific cell signaling pathways offer promising avenues for not only halting bone loss but also potentially reversing it.

Objective: This narrative review examines five emerging biological interventions: pulsed electromagnetic fields (PEMF), anti-Siglec-15 antibody (NP159), PARP14-dependent microglial signaling modulation, chronic intermittent hypobaric hypoxia (CIHH), and teriparatide alongside the mechanisms by which they shift cell signaling to prevent SCI-induced osteoporosis and promote spinal repair.

Search Methods: An online search of PubMed was conducted from 2021 to 2025 using the following keywords: “spinal cord injury,” “osteoporosis,” “osteoblast,” “osteoclast,” “PEMF,” “Siglec-15,” “PARP14,” “hypoxia,” “teriparatide,” “Nrf2,” “RANKL/OPG,” and “microglial polarization.”

Results: PEMF reactivated Wnt-beta-catenin signaling in rodent models following SCI, preserving cortical and trabecular bone mass and mechanical strength through osteoblast and osteocyte-mediated anabolism, without suppressing bone resorption.¹ Anti-Siglec-15 antibody (NP159) effectively prevented SCI-induced bone loss by blocking osteoclast maturation and resorptive activity while preserving osteoblastogenesis and OPG expression, yielding a net anabolic skeletal effect.² PARP14 knockdown studies demonstrated that PARP14 modulates microglial polarization from pro-inflammatory M1 to neuroprotective M2 states via the STAT1/6 pathway. Additionally, loss of PARP14 increased RANKL expression and pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6) which resulted in promoted osteoclast activity, indicating PARP14’s indirect role in limiting bone resorption.³ CIHH treatment activated hypoxia-inducible factor-1 alpha (HIF-1α) signaling, restoring bone mineral density (BMD) and trabecular architecture, decreasing osteoclast activity and bone resorptive markers (RANKL and TRAP), and increasing bone formation markers (ALP and OPG) in rodent SCI models. Teriparatide was shown to mitigate SCI-induced oxidative stress and enhance neurological recovery by increasing Nrf2 protein levels, which upregulated downstream antioxidant enzymes HO-1 and SOD-2, reducing reactive oxygen species (ROS) and providing an anabolic effect on bone mesenchymal stem cells. ⁵

Conclusions: The five reviewed interventions demonstrate that SCI-induced osteoporosis can be targeted at multiple signaling levels: anabolic bone promotion via PEMF, CIHH, and teriparatide; selective anti-resorption via anti-Siglec-15; and neuroinflammatory modulation via PARP14. Together, these findings suggest that optimal treatment of SCI-induced osteoporosis may lie in a sequenced combination strategy: first limiting neuroinflammation and osteoclast activity and then promoting anabolic bone formation. Future research should investigate how these pathways interact, particularly whether PARP14-mediated microglial modulation and teriparatide’s antioxidative effects converge on shared targets. Additionally, given teriparatide’s long-term risk for osteosarcoma, identifying alternative antioxidant-based therapies warrants further exploration.

Works Cited

1. Shao X, Yan Z, Wang D, et al. Pulsed Electromagnetic Fields Ameliorate Skeletal Deterioration in Bone Mass, Microarchitecture, and Strength by Enhancing Canonical Wnt Signaling-Mediated Bone Formation in Rats with Spinal Cord Injury. J Neurotrauma. 2021;38(6):765-776. doi:10.1089/neu.2020.7296
2. Peng Y, Langermann S, Kothari P, et al. Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats. JBMR Plus. 2023;7(12). doi:10.1002/jbm4.10825
3. Xu AH, Yang Y, Shao Y, Jiang MY, Sun YX. Poly(ADP-ribose) polymerase family member 14 promotes functional recovery after spinal cord injury through regulating microglia M1/M2 polarization via STAT1/6 pathway. Neural Regen Res. 2022;0(0):0. doi:10.4103/1673-5374.357909
4. Zhang L, Yin Y, Guo J, Jin L, Hou Z. Chronic intermittent hypobaric hypoxia ameliorates osteoporosis after spinal cord injury through balancing osteoblast and osteoclast activities in rats. Front Endocrinol (Lausanne). 2023;14. doi:10.3389/fendo.2023.1035186
5. Moliang X, Gangtong A, Yun F, et al. Teriparatide mitigates oxidative stress following spinal cord injury and enhances neurological recovery via the Nrf2/HO-1 signaling pathway. Front Pharmacol. 2025;16. doi:10.3389/fphar.2025.1538857