High dose teriparatide (rPTH1-34) therapy increases callus volume and enhances radiographic healing at 8-weeks in a massive canine femoral allograft model

  • PLoS One. 2017 Oct 11;12(10):e0185446. doi: 10.1371/journal.pone.0185446.
Kohei Nishitani  1  2 ,  Zachary Mietus  3 ,  Christopher A Beck  1  4  5 ,  Hiromu Ito  2 ,  Shuichi Matsuda  2 ,  Hani A Awad  1  3  4 ,  Nicole Ehrhart  6 ,  Edward M Schwarz  1  3  4
Affiliations
  • 1. Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United States of America.
  • 2. Department of Orthopaedics Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 3. Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States of America.
  • 4. Department of Orthopedics, University of Rochester Medical Center, Rochester, NY, United States of America.
  • 5. Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, United States of America.
  • 6. Department of Clinical Sciences, Colorado State University, Fort Collins, CO, United States of America.
PMID: 29020057 DOI: 10.1371/journal.pone.0185446
Abstract

Small animal studies have demonstrated significant high-dose recombinant parathyroid hormone1-34 (rPTH1-34) effects on intercalary allograft healing. Towards a human Adjuvant therapy to decrease non-unions, we evaluated rPTH1-34 safety and efficacy in a clinically relevant canine femoral allograft model. Adult female mongrel hounds (n = 20) received a 5cm mid-diaphyseal osteotomy reconstructed with a plated allograft, and were randomized to: 1) Placebo (n = 5; daily saline), 2) Continuous rPTH1-34 (n = 7; 5 μg/kg/day s.c. from day 1-55 post-op), or 3) Delayed rPTH1-34 (n = 8; 5 μg/kg/day s.c. from day 14-28 post-op). Safety was assessed by physical behavior and blood calcium monitoring. Cone beam CT (CB-CT) was performed on days 14, 28 and 56 post-op to assess 2D cortical healing, 3D bone volume, and Union Ratio. Biomechanical testing and dynamic histomorphometry were also performed. The high drug dose was poorly tolerated, as most dogs receiving rPTH1-34 had to be given intravenous saline, and one dog died from hypercalcemia. Continuous rPTH1-34 significantly increased 2D healing and callus volumes at 4-weeks versus Placebo, and sustained the significant increase in cortical union at 8-week (p<0.05). These rPTH1-34 effects were confirmed by histomorphometry, revealing significant increases in mineral apposition rates (MAR) on host bone and graft-host junctions (p<0.05). Delayed rPTH1-34 significantly increased callus volume and MAR at 8 weeks (p<0.05). Although no biomechanical differences were observed, as expected for early healing, the results demonstrated that 2D RUST scoring significantly correlated with torsional biomechanics (p<0.01). In conclusion, 8-weeks of intermittent high-dose rPTH1-34 treatment significantly increases callus formation and accelerates bony union of intercalary massive allografts in a clinically relevant canine model, but with serious side-effects from hypercalcemia.

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