Sclerostin Antagonism and the Osteocytes Role Prevention of Bone Loss after SCI

James J Peters Va Medical Center, Bronx NY

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Abstract

DESCRIPTION: At present, there is no practical treatment to prevent bone loss, or promote rebuilding of bone, in individuals with SCI. Regulation of Wnt signaling in bone by Wnt inhibitors (e.g., sclerostin, which is mainly produced by osteocytes) is crucial in the pathogenesis of osteoporosis, especially that due to disuse. In a recent phase I and II clinical trial, anti-sclerostin antibodie (Scl-Ab) increased bone mineral density (BMD) in postmenopausal women. In a pilot study we found that, when begun at 7 days after SCI and administered for 7 weeks, Scl-Ab almost completely prevented the SCI-induced reduction of BMD and partially preserved trabecular microarchitecture. Scl-Ab also increased osteoblastogenesis and decreased osteoclastogenesis of ex vivo cultured bone marrow progenitor cells. Thus, we have asked the following questions: 1) Whether Scl-Ab will completely prevent bone loss when its administration is begun immediately after SCI; 2) whether Scl-Ab is able to increase bone mass and strength when its administration is begun 28 days after SCI, when significant bone loss has already developed. In these proof of concept studies, Scl-Ab will be administered at 25 mg/kg/week, as was done in our preliminary work. In addition, a pilot study is proposed to explore the effect of the administration of a lower, more clinically relevant dose of Scl-Ab to reduce SCI-related bone loss. The mechanisms underlying bone loss in response to mechanical unloading in general, and after SCI in particular, remain poorly understood. Osteocytes compose 90% to 95% of all bone cells, and they have been considered as an orchestrator of bone remodeling through regulation of osteoclast and osteoblast activity by transducing mechanical signals into chemical signals. Importantly, we showed abnormalities of osteocyte morphology in ovarectomized (OVX) rats, and treatment of OVX with Scl-Ab greatly improved osteocyte morphology. Thus, we hypothesize that pathological changes in osteocytes are likely a central cause for bone loss in SCI animals, and that restoration of osteocyte structure and function by Scl-Ab will rescue SCI related- bone loss. To address these questions and hypotheses three specific aims are proposed: Aim 1. To perform proof of concept studies to evaluate the ability of Scl-Ab to preserve bone integrity after SCI. Aim 1a) To test whether initiating Scl-Ab at the time of SCI protects completely against bone loss due to SCI. Scl-Ab at 25 mg/kg/week will begin within one hour after SCI and be continued for 2 months. The key endpoints to be determined will be bone mass, microarchitecture, strength, blood and histomorphometric markers for bone formation and resorption, and osteoblastogenesis and osteoclastogenesis of bone marrow progenitors. Aim 1b) To evaluate the ability of Scl-Ab to reverse bone loss when initiated 1 month after SCI. Scl-Ab will be initiated 28 days after SCI and continued for 1, 4 or 8 weeks. Aim 2. To conduct a pilot study to test the ability of lower doses of Scl-Ab to reduce SCI-related bone loss. A similar approach to that proposed Aim 1a will be employed, except that Scl-Ab will be administered at two lower doses (3 or 9 mg/kg/month). This work will provide initial insight as to the minimum effective dose of Scl-Ab capable of maintaining therapeutic efficacy at the lowest cost for clinica care. Aim 3. To test whether impairment of osteocyte function is one mechanism by which SCI causes bone loss, and whether restoration of normal osteocyte function is a mechanism by which Scl-Ab rescues such bone loss. The functional properties of osteocytes in animals from Aim 1 study will be characterized by analysis of: i) osteocyte morphology; ii) osteocyte number and apoptosis; iii) osteocytic gene and protein expression; and iv) key factors involved in bone mechanotransduction pathway. The above studies will be the first study to systematically evaluate the efficacy of Scl-Ab to prevent or reverse bone loss after SCI and to explore how Scl-Ab regulates osteocyte function. If the results are as expected, Scl-Ab might offer the first hope of a novel potent agent to improve bone health in SCI patients.