Sclerostin Inhibition Prevents Spinal Cord Injury-Induced Cancellous Bone Loss

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 ¼ 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 þ TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI þ 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 mCT and histomorphometry) and distal femur (via mCT), 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 þ Scl-Ab and SCI þ 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.

Application of anti-Sclerostin therapy in non-osteoporosis disease models

“…(22, 25) These data suggest that at least in both normal bone and post-menopausal osteoporosis, Sclerostin inhibition is both anabolic and anti-resorptive, mirroring the effect on bone of increased loading. Similar improvements in bone density from Sclerostin antibody therapy have been seen in mouse and rat models of disuse related bone loss and spinal cord injury (27–31). These exciting findings raised the question of whether anabolic Sclerostin antibody therapy could be equally effective at treating genetic and metabolic disorders of bone.…”

Fructose consumption does not worsen bone deficits resulting from high-fat feeding in young male rats

“…[29–31] Images were acquired using the following parameters: 80kVP/120μA, 0.5mm aluminium filter, 1k camera resolution, 19.2μm voxel size, 0.5° rotation step, and 180° tomographic rotation. The cancellous regions of interest (ROI) at the distal femoral metaphysis began 1.5mm proximal to the growth plate and encompassed 4mm, including the sponge-like trabecular (cancellous) bone spicules in the medullary cavity and excluding the dense compact (cortical) bone that surrounds the medullary cavity.…”

Locomotor training with adjuvant testosterone preserves cancellous bone and promotes muscle plasticity in male rats after severe spinal cord injury

“…In comparison, only a few studies have examined musculoskeletal adaptations occurring after severe contusion SCI (Lin et al, ; Otzel, Conover, et al, ; Phillips et al, ; Voor et al, ; Ye et al, ), a model that is indicative of the severely impaired incomplete SCI population and that is not typically associated with recovery of hindlimb bone or muscle parameters or the ability to perform hindlimb stepping (Otzel, Conover, et al, ). Our laboratory has developed a rodent severe contusion SCI model, that displays several characteristics of the severe incomplete SCI population, including the complete inability to support the hindlimbs in stance or to perform voluntary over‐ground stepping for at least 3 months postinjury, extensive cancellous bone deficits at the distal femur and proximal tibia (Otzel, Conover, et al, ), and ~50% lower circulating testosterone than uninjured controls for upwards of 2 months postinjury (Beggs et al, ; Otzel, Conover, et al, ; Yarrow, Conover, et al, ). Using this model, we have reported a >50% reduction in soleus muscle fiber cross‐sectional area (fCSA) occurs within 21 days of SCI, although we did not observe definitive signs of the hallmark slow‐oxidative to fast‐glycolytic fiber‐type transition at this relatively early postinjury time point (Phillips et al, ).…”