The clinical management of critical (>3cm) defects in bone from traumatic injuries remains a major challenge for both amputation and limb salvage cases. Thus, the quest for a practical adjuvant therapy, such as teriparatide (PTH{1-34}), remains a high priority. Despite extensive work concluding that PTH{1-34} is effective in small animal models of fracture healing, success in translating this technology into a human therapy remains elusive. To this end we have made remarkable progress during the initial funding period of this CORT by developing a computerized tomography (CT) outcome measure (Union Ratio) that correlates with torsional biomechanics;and clinical cone beam (CB) CT with metal artifact suppression to quantify massive allograft healing in dogs and humans. Now we propose to perform a definitive large animal study (canine femoral defect), with translational outcome measures to formally establish PTH{1-34} efficacy in a clinically relevant model of challenging bone healing. Two cohorts of skeletally mature dogs will be studied to evaluate PTH{1-34} effects on femoral allograft healing.
In Aim 1 the dogs will be randomized to placebo or PTH{1-34} treatments, followed by longitudinal CB-CT, and sacrificed at 8-weeks or 6-months to assess eariy and mature allograft healing. The primary outcome will establish PTH{1-34} effects on ex vivo torsional biomechanics (stiffness and torque to failure), and the secondary outcomes, including histomorphometry. will establish PTH{1-34} effects on in vivo radiology (Union Ratio and bone volume).
In Aim 2 we will use these data to demonstrate that the Union Ratio correlates significantly with fracture healing (torsional biomechanics) compared to the current clinical standard of subjective x-ray scoring. Finally, in Aim 3 we will complete the ongoing clinical pilot of the natural history of human massive allograft healing determined by CB-CT at 0.5, 8 and 18-months. Union Ratios will be quantified from these data to derive a power calculation for a PTH{1-34} efficacy clinical trial in limb salvage patients.

Public Health Relevance

The clinical management of critical (>3cm) defects in bone from traumatic injuries remains a major challenge for both amputation and limb salvage cases, which continue to have poor outcomes despite their great costs. Based on the remarkable preclinical results of teriparatide (PTH{1-34}) in rodent models of bone healing, and anecdotal evidence from off-label treatment of fracture non-union patients, here we propose a definitive large animal study to formally prove whether or not this drug is useful as an adjuvant therapy for massive allografting of critical defects in bone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR054041-07
Application #
8531859
Study Section
Special Emphasis Panel (ZAR1-KM)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
7
Fiscal Year
2013
Total Cost
$360,077
Indirect Cost
$113,940
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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