Deferoxamine Restores Callus Size, Mineralization, and Mechanical Strength in Fracture Healing after Radiotherapy

Abstract

Background Therapeutic augmentation of fracture site angiogenesis with Deferoxamine (DFO) has proven to increase vascularity, callus size and mineralization in long-bone fracture models. We posit that the addition of DFO would enhance pathological fracture healing in the setting of radiotherapy in a model where non-unions are the most common outcome. Methods Sprague-Dawley rats (n = 35) were divided into 3 groups. Fracture (Fx), radiated fracture (XFx) and radiated fracture + DFO (XFxDFO). Groups XFx and XFxDFO received a human equivalent dose of radiotherapy (7 Gy/day × 5 days = 35 Gy) 2 weeks prior to mandibular osteotomy and external fixation. The XFxDFO group received injections of DFO into the fracture callus after surgery. Following a 40-day healing period, mandibles were dissected, clinically assessed for bony-union, imaged with Micro-CT, and tension tested to failure. Results Compared to radiated fractures, metrics of callus size, mineralization and strength in DFO treated mandibles were significantly increased. These metrics were restored to a level demonstrating no statistical difference from control fractures. In addition we observed an increased rate of achieving bony unions in the XFxDFO treated group when compared to XFx (67% vs. 20% respectively). Conclusions Our data demonstrate near total restoration of callus size, mineralization, and biomechanical strength, as well as a 3-fold increase in the rate of union with the use of DFO. Our results suggest that the administration of DFO may have the potential for clinical translation as a new treatment paradigm for radiation induced pathologic fractures. Level of Evidence Animal study, not gradable for level of evidence.

Clinical Use of Deferoxamine in Distraction Osteogenesis of Irradiated Bone

“…This still resulted in severe maxillary hypoplasia and our observations do parallel experimental data regarding potential beneficial effects of deferoxamine in the context of DO and radiation. (17, 27, 28) Numerous questions remain unanswered, such as ideal dosing, timing of deferoxamine, etc. Nonetheless, we hope that our experience promotes further clinical use and critical assessment of outcomes of deferoxamine in the context of DO and irradiated craniofacial bone.…”

Amifostine Preserves Osteocyte Number and Osteoid Formation in Fracture Healing Following Radiotherapy

“…Utilizing this animal model, we have examined the degree by which radiotherapy impedes fracture site mineralization and vascularity as measured with μCT imaging, and the limits of biomechanical integrity as quantified with biomechanical tension testing in the rat mandible. 16-17,27-28 …”

“…16 The selection of this particular model was based on our collective experience accumulating over 10 years of data related to the pathologic effects of radiation on fracture site healing in the rat mandible. Our previous investigations demonstrated quantifiably diminished metrics of vascular density, bone quality and biomechanical strength 16-17 . Here we investigate the effect of radiotherapy on the cellular environment of the fracture site.…”

The role of PGRN in musculoskeletal development and disease

“…Considering its broad range of biological functions as a multi-factorial progenitor growth hormone, the precise identification of its binding domains and the therapeutic implementation of a biologically specific and effective engineered molecule could provide a pharmaceutical alternative to the current available treatment options in rheumatoid arthritis, osteoarthritis, osteomyelitis, and may possibly constitute an alternative to proposed therapies accelerating fracture healing, such as parathyroid hormone–related peptide (PTHrP) (80), and also the recently proposed deferoxamine (81). …”