Sclerostin Antibody Reverses the Severe Sublesional Bone Loss in Rats After Chronic Spinal Cord Injury

Abstract

To date, no efficacious therapy exists that will prevent or treat the severe osteoporosis in individuals with neurologically motor-complete spinal cord injury (SCI). Recent preclinical studies have demonstrated that sclerostin antibody (Scl-Ab) can prevent sublesional bone loss after acute SCI in rats. However, it remains unknown whether sclerostin inhibition reverses substantial bone loss in the vast majority of the SCI population who have been injured for several years. This preclinical study tested the efficacy of Scl-Ab to reverse the bone loss that has occurred in a rodent model after chronic motor-complete SCI. Male Wistar rats underwent either complete spinal cord transection or only laminectomy. Twelve weeks after SCI, the rats were treated with Scl-Ab at 25 mg/kg/week or vehicle for 8 weeks. In the SCI group that did not receive Scl-Ab, 20 weeks of SCI resulted in a significant reduction of bone mineral density (BMD) and estimated bone strength, and deterioration of bone structure at the distal femoral metaphysis. Treatment with Scl-Ab largely restored BMD, bone structure, and bone mechanical strength. Histomorphometric analysis showed that Scl-Ab increased bone formation in animals with chronic SCI. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increased Tcf7, ENC1, and the OPG/RANKL ratio expression, and decreased SOST expression. Our findings demonstrate for the first time that Scl-Ab reverses the sublesional bone loss when therapy is begun after relatively prolonged spinal cord transection. The study suggests that, in addition to being a treatment option to prevent bone loss after acute SCI, sclerostin antagonism may be a valid clinical approach to reverse the severe bone loss that invariably occurs in patients with chronic SCI.

Spinal Cord Injury as a Model of Bone-Muscle Interactions: Therapeutic Implications From in vitro and in vivo Studies

“…Untreated SCI mice showed a significant reduction in BMD and the deterioration of bone structure at the distal femoral metaphysis. These data suggest that sclerostin antagonism might be a viable therapeutic option not only to prevent bone loss after acute SCI but also in the chronic setting (19).…”

“…Murine SCI models showed that anti-sclerostin antibodies could preserve the osteocyte morphology and structure, blocking the skeletal deterioration after either motor-incomplete (18) or motor-complete SCI (15). A recent study assessed the efficacy of these antibodies in reversing the bone loss in a rodent model after motor-complete SCI (19). Animals treated with 25 mg/kg/week for 8 weeks (starting at 12 weeks after SCI) showed a significant increase in BMD, structure, and mechanical strength.…”

Administration of Denosumab Preserves Bone Mineral Density at the Knee in Persons With Subacute Spinal Cord Injury: Findings From a Randomized Clinical Trial

“…Preclinical studies of sclerostin antagonism or genetic ablation in acute and chronic rodent models of SCI have been performed by our group. (47)(48)(49) In a rat model, anti-sclerostin antibody (reagent provided by Amgen) was begun 7 days after spinal cord transection (significant bone loss occurs as early as 7 days after SCI in the rat model) and the agent was then administered weekly over the next 7 weeks; sclerostin antagonism completely prevented and/or reversed the marked bone loss that occurred in the untreated spinal cord transected animals. (47) Sclerostin knockout mice (animals were provided by Amgen) that underwent spinal cord transection were protected from the severe sublesional bone loss that occurred in WT mice with spinal cord transection.…”

“…( 48 ) To test whether sclerostin antagonism could reverse bone loss in rats after chronic motor‐complete SCI, treatment was initiated with anti‐sclerostin antibody or vehicle 12 weeks after spinal cord transection and continued for 8 weeks. ( 49 ) In SCI rodents that received normal saline injections, there was significant reduction in BMD, estimated bone strength, and deterioration of bone structure at the distal femoral metaphysis at 20 weeks, whereas animals that received anti‐sclerostin antibody had remarkably restored BMD, bone structure, and bone mechanical strength. ( 49 ) Because the Wnt signaling system is inhibited in preclinical models of SCI because of increases in two inhibitors of this signaling pathway, sclerostin and Dickkopf‐related protein 1 (DKK1), ( 50 ) it may be speculated that treatment restoring this vital skeletal pathway to a more normal level of activity would be more favorable to bone health than merely suppressing osteoclast function.…”

Icaritin promotes the osteogenesis of bone marrow mesenchymal stem cells via the regulation of sclerostin expression

“…on Wnt pathway. Antagonism or loss of the SOST will result in elevated bone formation and a high bone mass (19,20). The SOST antibody (SclAb) has attracted attention as an anabolic strategy for treating post-menopausal osteoporosis (21).…”