PRS PSRC Podium Proofs 2016
Michael D. Uyeda, MD
From the University of California, Los Angeles, Los Angeles, Calif.
PURPOSE: Osteoporosis affects more than 200 million people worldwide. Current antiresorptive treatments have significant limitations because of systemic side effects. NELL-1 is a potent cytokine with combined proosteogenic and antiosteoclastic effects. Previous systemic administration studies using PEGylated NELL-1(NELL-PEG) showed increased bone quality and quantity in healthy mice given 1.25 mg/kg intravenously every 7 days. This study aims to reduce NELL-PEG injection frequency to 14 days while using more patient-friendly intraperitoneal (IP) administration route to recover bone in OVX-induced osteoporotic mice.
METHODS: Three-month-old female BALB/c mice underwent ovariectomy (OVX; n = 10) or Sham operation (n = 10). Osteoporosis induction was confirmed using dual-energy x-ray absorptiometry and ex vivo micro computed tomography (CT) scans. Twelve 5-week-post-OVX BALB/c mice underwent NELL-PEG treatment every 2 weeks with dosages of (1) 5 mg/kg IP or (2) 10 mg/kg IP and harvested at 8 weeks. Serum was analyzed at 0, 4, and 8 weeks. Dynamic BMD was measured by dual-energy x-ray absorptiometry. Ex vivo micro CT, colony-forming unit assay, and histology were performed after harvest.
RESULTS: Ovariectomy was confirmed by decreased BMD (7%) and BV/TV (39.3%). Systemic NELL-PEG at 10 mg/kg IP increased BMD in distal femur (13%), proximal tibia (14%), and lumbar vertebrae (15%). Micro CT data showed the same trend in BMD, BV/TV, and trabecular structures. Colony-forming unit assay confirmed greater osteogenesis in bone marrow stem cells flushed from 10 mg/kg delivery than 5 mg/kg group, and histology confirmed increased bone formation in both treatment groups.
CONCLUSIONS: Systemic NELL-PEG therapy regenerates bone in osteoporotic mice when administered at 10 mg/kg dosage via IP administration every 2 weeks. Systemic NELL-PEG may be applied to improve overall bone architecture and potentially enhance postsurgical craniofacial and alveolar bone healing.