UCLA

Vertebral Implantation of NELL-1 Enhances Bone Formation In Osteoporotic Sheep

By

Michael Ming-Ying Chiang

Master of Science in Oral Biology

University of California, Los Angeles, 2013

Professor Shen Hu, Co-Chair

Professor Xinli Zhang, Co-Chair

Background: Vertebral compression fractures related to osteoporosis greatly afflict the aging population. The most commonly used therapy today is balloon kyphoplasty, a procedure that involves the inflation of a balloon and injection of cement such as polymethyl methacrylate. However, this treatment is far from ideal as it is associated with significant side effects, including local toxicity and rare systemic complications. NELL-1, a secreted osteoinductive factor that possesses both pro-osteogenic and anti-resorptive properties, is a promising candidate for an alternative to current treatment modalities. The use of NELL-1 in balloon kyphoplasty might improve post surgical outcome for over 10 million osteoporotic American who are susceptible to vertebral compression fractures. The present study utilizes the pro-osteogenic properties of recombinant human NELL-1 (rhNELL-1) in lumbar spine balloon kyphoplasty using an osteoporotic sheep model.

Methods: Osteoporosis in N=8 sheep was induced through ovariectomy, dietary depletion of calcium and vitamin D, and steroid administration. After osteoporotic induction was confirmed by dual-energy X-ray absorptiometry (DXA), balloon kyphoplasty was performed in N=6 sheep with significant osteopenia. Sheep were randomly implanted with the control vehicle, comprised of hyaluronic acid (HA), hydroxyapatite, and β-tricalcium phosphate (β-TCP), or the treatment material of rhNELL-1 protein lyophilized onto β-TCP mixed with HA. Analysis of lumbar spine healing was performed by radiographic, histologic, and biomechanical testing.

Results: rhNELL-1 treatment significantly increased lumbar spine bone formation, as determined by bone mineral density, fractional bone volume, and mean cortical width by micro-computed tomography. Histological analysis revealed a significant increase in bone area as well as osteoblast number and decrease in osteoclast number around the implant site. Biomechanical properties of trabecular bone were analyzed using Finite Element Analysis (FEA), demonstrating that rhNELL-1-treatment resulted in a significantly more stress-resistant composition.

Conclusion: Our findings suggest rhNELL-1-based balloon kyphoplasty successfully improved cortical and cancellous bone regeneration in the lumbar spine of osteoporotic sheep. Thus, rhNELL-1 based balloon kyphoplasty represents a potential new anabolic, anti-resorptive local therapy for treating osteoporotic bone loss and/or fractures.