270,000 individuals currently have a spinal cord injury (SCI) in the US. 100% of those with functionally- complete SCIs experience sublesional osteoporosis, underlying the 100-fold greater bone fracture risk after SCI. Current bone loss treatments, including bisphosphonates (a frontline pharmacologic treatment) and exercise only slow bone loss after SCI, but do not regenerate sublesional bone mass. As such, need exists for novel bone regenerative therapies following SCI. Recently, a pharmacologic """"""""anti-sclerostin"""""""" antibody (Sclerostin-Ab) has been developed that produces profound osteoanabolic effects by negating endogenous sclerostin (a negative regulator of the Wnt-signaling pathway that promotes osteoblast development and bone formation). The effectiveness of Sclerostin-Ab is demonstrated by its ability to reverse 1-year of ovariectomy- induced bone loss in rats with only 3 weeks of treatment and by its ability to completely prevent bone loss subsequent to hind limb unloading. A clinical version of Sclerostin-Ab (AMG 785) has also been shown to increase spine and hip BMD by 3-5% within 85 days of a single treatment dose. Importantly, sclerostin is elevated after functionally-complete SCI, suggesting that it plays a role in SCI-induced bone loss;however, no study has evaluated the efficacy of Sclerostin-Ab after SCI. It is essential to examine whether Sclerostin-Ab is able to regenerate bone in a pre-clinical model before promoting it to clinical trials in thi population. Few models of chronic SCI-induced bone loss exist within the literature. The current models utilize spinal cord transection or young (non-skeletally mature) rodents, limiting their clinical relevance. In contrast, we have developed a mid-thoracic contusion SCI model (utilizing skeletally-mature male rodents) that exhibits extensive cancellous bone loss acutely after injury. Further development of this model is required to determine whether it exhibits the chronic cortical bone deficits that are a hallmark characteristic of clinical bone loss after SCI. For thi proposal, we will 1) expand upon our current acute SCI bone loss model in order to develop a clinically-relevant model of chronic SCI-induced bone loss (addressing the weaknesses of the existing models) and 2) determine whether Sclerostin-Ab regenerates bone in this model. In order to do so, we will assess: cortical and cancellous bone mass (via ?CT), bone turnover (via histomorphometry), bone strength (via mechanical strength tests), and sclerostin expression at 1, 2, and 4 months after severe mid-thoracic contusion SCI (or Sham surgery) in order to determine the time of peak cortical bone loss after SCI. We will then evaluate whether Sclerostin-Ab regenerates bone when administered at the time of peak cortical bone loss in this model. In support of this proposal, we have obtained Sclerostin-Ab from Amgen through a VA Cooperative Research and Development Agreement (CRADA). Our primary hypotheses are that 1) rats will experience progressive bone loss after SCI that is characterized by the early loss of cancellous bone and a delayed loss of cortical bone and 2) Sclerostin-Ab will regenerate bone and improve bone strength in a rodent model of chronic SCI-induced bone loss. In order to test these hypotheses, the following Specific Aims will be evaluated:
AIM 1 : Characterize the acute and chronic bone deficits in skeletally-mature male rodents after severe mid- thoracic contusion SCI in order to develop a clinically-relevant model of chronic SCI-induced bone loss.
AIM 2 : Determine whether Sclerostin-Ab is capable of regenerating hind limb bone mineral characteristics and bone strength in a rodent model of chronic SCI that exhibits severe cortical and cancellous bone deficits. This proposal will expand upon our acute SCI model that exhibits severe cancellous bone loss in order to develop a clinically-relevant chronic SCI model that exhibits cortical and cancellous bone loss (addressing the weaknesses of the existing models) and will provide the first-ever direct evidence regarding the ability of Sclerostin-Ab to regenerat bone after SCI. These findings will provide proof-of-principle for future clinical trials intended o assess the efficacy of Sclerostin-Ab as a means of regenerating bone in Veterans with SCI.
More than 42,000 individuals with spinal cord injury (SCI) are eligible for treatment in the VA Healthcare System (i.e., 16% of the entire SCI population), resulting in direct healthcare expenditures exceeding $716 million/year. 100% of those with functionally-complete SCIs experience sublesional osteoporosis, underlying the 100-fold greater bone fracture risk that occurs after SCI. No known therapy is able to regenerate bone after SCI and no clinical guidelines currently address treatment of bone loss after SCI. Despite this >40% of VA SCI Physicians report prescribing bisphosphonates for SCI-induced bone loss. However, long-term bisphosphonate therapy only slows bone loss after SCI, but does not stop bone demineralization or regenerate sublesional bone mass. The extensive bone loss and high fracture risk in this population represent fundamental impediments to rehabilitation strategies intended to maximize physical function after SCI. The above results underlie the importance of identifying novel treatments capable of regenerating within this population.
|Beggs, Luke A; Ye, Fan; Ghosh, Payal et al. (2015) Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss. J Bone Miner Res 30:681-9|
|Yarrow, J F; Ye, F; Balaez, A et al. (2014) Bone loss in a new rodent model combining spinal cord injury and cast immobilization. J Musculoskelet Neuronal Interact 14:255-66|