Neurogenic bone loss after SCI: skeletal rehabilitation via Wnt and exercise interactions

点击翻译按钮获取中文摘要

The purpose of this application is to identify a long-term rehabilitative solution to skeletal fragility associated with spinal cord injury (SCI). SCI is one of the most debilitating medical conditions among the veteran population. Neurogenic osteopenia is a major complicating factor for SCI rehabilitation efforts, and there is currently a paucity of options for treating bone wasting associated with SCI. Thus, an urgent need exists to develop new rehabilitative strategies for preserving and/or restoring bone lost to SCI. This is particularly true given that significant advances are being made in neuromuscular rehabilitation (e.g., harnessing motoneuron plasticity and sprouting/regeneration mechanisms) for functional restoration; all of those efforts are in jeopardy if they are not accompanied by restoration of bone structure and strength, as fractures can nullify progress made in neurological rehabilitation. Although neurogenic bone loss is a different disease than standard postmenopausal osteoporosis (PMO) or senile osteoporosis, there are no approved therapies that specifically target the sequelae of SCI-induced bone loss. The closest drug option for SCI-induced bone loss is the sclerostin neutralizing antibody Romosozumab (“Romo”), due to its potent anabolic action and efficacy in mouse models of SCI. However, Romo received a black box warning from the FDA cautioning its use in patients at higher risk for cardiovascular disease and stroke, two risk factors that are significantly elevated in SCI patients. Therefore, while the bone-building effects of Romo are beneficial in SCI, its use at full strength is not suitable for SCI patients. We have found a combination therapy (sclerostin and Dkk1 neutralization) that reduces the sclerostin antibody dose by 83% (and total drug dose by 75%) yet still maintains all of the osteoanabolic action of full strength sclerostin antibody. Our overall goal is to is capitalize on the interaction between a very specific and novel osteoanabolic therapy (identified in our lab), and the powerful, lasting effects of mechanical stimulation (exercise), to define a rehabilitative strategy for neurogenic bone loss that will have lasting effects beyond the short-lived windows of most pharmaceutical options. Our approach takes into consideration the risk factors associated with SCI (e.g., elevated cardiovascular complications and stroke) and the beneficial effects of exercise to both the skeleton and to motor function to design a more tailored and focused approach to skeletal rehabilitation after SCI. In the first aim, we will determine whether an optimized ratio of sclerostin/Dkk1 antibody treatment can restore skeletal density, size, and strength after neurogenic bone loss from SCI. In the second aim, we will determine whether optimized sclerostin/Dkk1 antibody treatment can sensitize bone to the effects of mechanical exercise after SCI, producing a more robust and fracture-resistant skeleton. In the third aim, we will determine whether continued mechanical stimulation can maintain the beneficial skeletal effects of discontinued sclerostin/Dkk1 antibody treatment, ultimately providing a long-term, non-pharmacologic solution to skeletal maintenance after SCI. We will simultaneously assess motoneuron and skeletal muscle recovery, and functional/behavioral outcomes to evaluate the effect of the therapy on neuronal and muscle recovery. As (1) the activation of Wnt signaling and (2) exercise are both therapeutic for axonal regeneration, myogenesis, and skeletal health, the approach we propose is likely to have multi-systems benefit in SCI patients.