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Updated: Apr 21, 2026
Longitudinal Evaluation of Mouse Hind Limb Bone Loss After Spinal Cord Injury using Novel, in vivo, Methodology
Published on: December 7, 2011
Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss
Luke A Beggs1, Fan Ye, Payal Ghosh
1Research Service, Department of Veterans Affairs Medical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA; Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
Abstract:
Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n = 11-19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via μCT and histomorphometry) and distal femur (via μCT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population.
Insights
Sclerostin antibody treatment prevents bone loss after spinal cord injury (SCI) by promoting bone formation. This approach may offer a new therapy for osteoporosis in SCI patients.
Area of Science:
- Orthopedics
- Endocrinology
- Regenerative Medicine
Background:
- Spinal cord injury (SCI) leads to significant bone loss below the injury site.
- Sclerostin, a protein that inhibits bone formation, increases after SCI, potentially driving this bone loss.
- The efficacy of inhibiting sclerostin to counteract SCI-induced bone loss is not well understood.
Purpose of the Study:
- To investigate if a sclerostin antibody (Scl-Ab) can prevent hindlimb bone loss in a rodent model of SCI.
- To compare the effects of Scl-Ab with testosterone enanthate (TE), a known agent that prevents SCI-induced bone loss.
Main Methods:
- Male Sprague-Dawley rats underwent SHAM surgery, SCI, SCI+TE, or SCI+Scl-Ab treatment for three weeks.
- Bone loss was assessed using micro-CT and histomorphometry of the proximal tibia and distal femur.
- Cortical bone strength was evaluated in the femoral diaphysis.
Main Results:
- SCI caused significant reductions in cancellous bone volume, trabecular number, thickness, and connectivity in the hindlimbs.
- Both Scl-Ab and TE prevented SCI-induced cancellous bone loss.
- Scl-Ab demonstrated anabolic effects by increasing osteoblast surface and bone formation, while TE showed antiresorptive effects by reducing osteoclast surface.
- Only Scl-Ab completely preserved cortical bone strength.
Conclusions:
- Sclerostin inhibition is effective in preventing both cancellous and cortical bone loss following SCI.
- Scl-Ab treatment offers a promising therapeutic strategy for managing osteoporosis in SCI individuals.
- These findings support further clinical trials to evaluate Scl-Ab for SCI-related bone loss.
