Teriparatide (recombinant parathyroid hormone 1-34) enhances bone allograft integration in a clinically relevant pig model of segmental mandibulectomy

Abstract

Massive craniofacial bone loss poses a clinical challenge to maxillofacial surgeons. Structural bone allografts are readily available at tissue banks but are rarely used due to a high failure rate. Previous studies showed that intermittent administration of recombinant parathyroid hormone (rPTH) enhanced integration of allografts in a murine model of calvarial bone defect. To evaluate its translational potential, the hypothesis that rPTH would enhance healing of a mandibular allograft in a clinically relevant large animal model of mandibulectomy was tested. Porcine bone allografts were implanted into a 5-cm-long continuous mandible bone defect in six adult Yucatan minipigs, which were randomized to daily intramuscular injections of rPTH (1.75 μg/kg) and placebo (n = 3). Blood tests were performed on Day 56 preoperation, Day 0 and on Day 56 postoperation. Eight weeks after the surgery, bone healing was analyzed using high-resolution X-ray imaging (Faxitron and micro computed tomography [CT]) and three-point bending biomechanical testing. The results showed a significant 2.6-fold rPTH-induced increase in bone formation (p = 0.02). Biomechanically, the yield failure properties of the healed mandibles were significantly higher in the rPTH group (yield load: p < 0.05; energy to yield: p < 0.01), and the post-yield displacement and energy were higher in the placebo group (p < 0.05), suggesting increased mineralized integration of the allograft in the rPTH group. In contrast to similar rPTH therapy studies in dogs, no signs of hypercalcemia, hyperphosphatemia, or inflammation were detected. Taken together, we provide initial evidence that rPTH treatment enhances mandibular allograft healing in a clinically relevant large animal model.

Keywords: mandible; parathyroid hormone; reconstruction; structural allograft.

Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest.

© 2020 John Wiley & Sons, Ltd.

Figures

Figure 1:. Mandible bone reconstruction using allografts in a minipig model.

(A) Five-cm-long mandibular bone allografts harvested from minipigs. (B) Processed bone allografts. (C) Intraoral image of the right side of the mandible after teeth extraction. (D) Intraoral image of healed gingivae 8 weeks post-extractions. (E) Five-cm-long osteotomy in the right side of the mandible. Bone stabilized with a locking plate and screws. (F) 3D CT image of a minipig mandible post-osteotomy. (G) Mandible allograft placed within the defect site. The allograft is secured in its location by two locking screws. (H) Fluoroscopic image showing the allograft in place following surgery.

Figure 2:. High resolution X-ray images of right hemimandibles.

A Faxitron scanner was used to image surgically treated hemimandibles after the animals had been euthanized. Mandible allografts are seen at the defect site with variable amounts of new bone surrounding them.

Figure 3:. 3D micro-CT images of treated bone defects.

(A) 3D micro-CT scan of a mandibular allograft prior to implantation. (B) Hemimandibles were trimmed after Faxitron imaging and scanned using a micro-CT system. Allografts are highlighted in yellow, new bone in red, and host bone in blue. Note the signs of remodeling in two allografts in the PTH group and advanced resorption of one allograft in the PBS group. (C) Total bone volume at the defect site was quantified based on findings on micro-CT scans, showing greater bone volume in the PTH group than in the PTH group. (D) New bone volume at the defect site was manually contoured and quantified based on micro-CT scans, showing greater new bone volume in the PTH group than in the PTH group. (E) A higher level of bone mineral density of the total bone volume was calculated in the PBS group. (F) Similar level of bone mineral density was calculated in the new bone generated within the bone defects. (unpaired two-tailed t-test; graphs represent means and SEMs; n=3 per group).

Figure 4:. Quantitative results of laboratory tests.

Blood was taken from the minipigs during the: extraction (Day 56 pre-op), osteotomy (Day 0) and at euthanasia (Day 56 post-op), to assess (A) calcium, (B) phosphate, (C) percentage of neutrophils, and (D) number of white blood cells. Note that no differences between groups were observed (two-way ANOVA with repeated measures; graphs represent means and SEMs).

Diagram 1.

Experimental Design