Abaloparatide, a PTH receptor agonist with homology to PTHrP, enhances callus bridging and biomechanical properties in rats with femoral fracture.

Fractures typically heal via endochondral and intramembranous bone formation, which together form a callus that achieves union and biomechanical recovery. PTHrP, a PTH receptor agonist, plays an important physiological role in fracture healing as an endogenous stimulator of endochondral and intramembranous bone formation. Abaloparatide, a novel systemically-administered osteoanabolic PTH receptor agonist that reduces fracture risk in women with postmenopausal osteoporosis, has 76% homology to PTHrP, suggesting it may have potential to improve fracture healing. To test this hypothesis, ninety-six 12-week-old male rats underwent unilateral internally-stabilized closed mid-diaphyseal femoral fractures and were treated starting the next day with daily s.c. saline (Vehicle) or abaloparatide at 5 or 20 µg/kg/d for 4 or 6 weeks (16 rats/group/time point). Histomorphometry and histology analyses indicated that fracture calluses from the abaloparatide groups exhibited significantly greater total area, higher fluorescence scores indicating more newly-formed bone, and higher fracture bridging scores versus Vehicle controls. Callus bridging score best correlated with callus cartilage score (r = 0.64) and fluorescence score (r = 0.67) at week 4, and callus area correlated with cartilage score (r = 0.60) and fluorescence score (r = 0.89) at Week 6. By micro-CT, calluses from one or both abaloparatide groups had greater bone volume, bone volume fraction, bone mineral content, bone mineral density, and cross-sectional area at both time points versus Vehicle controls. Destructive bending tests indicated greater callus maximum load and stiffness in one or both abaloparatide groups at both time points versus Vehicle controls. These results provide preliminary preclinical evidence for improved fracture healing with systemically-administered abaloparatide. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Abaloparatide, a novel osteoanabolic PTHrP analog, increases cortical and trabecular bone mass and architecture in orchiectomized rats by increasing bone formation without increasing bone resorption.

Male osteoporosis can occur with advanced age and with hypogonadism, with increased bone resorption and/or inadequate bone formation contributing to reduced bone mass and increased fracture risk. Abaloparatide is a selective PTH receptor agonist that increases bone formation and bone mass in postmenopausal women with osteoporosis and in estrogen-deficient animals. The current study evaluated the effects of abaloparatide in orchiectomized (ORX) rats, a model of male osteoporosis. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery; 8 weeks later the ORX groups exhibited relative osteopenia vs sham controls, based on dual X-ray absorptiometry (DXA) and/or peripheral quantitative computed tomography (pQCT) assessments at the total body, lumbar spine, femur, and tibia. ORX rats (n = 10/group) were then injected daily (s.c.) for 8 weeks with vehicle or abaloparatide at 5 (ABL5) or 25 µg/kg/d (ABL25). Sham controls (n = 10) received s.c. vehicle. DXA and pQCT showed that one or both abaloparatide groups gained more areal and volumetric BMD at all sites analyzed compared with vehicle controls, leading to substantial or complete reversal of ORX-induced BMD deficits. pQCT also indicated greater gains in tibial cortical thickness in both abaloparatide groups versus vehicle controls. Tibial bone histomorphometry showed greater trabecular bone formation and bone volume and improved micro-architecture with abaloparatide, with no increase in osteoclasts. Abaloparatide also led to significant improvements in the balance of biochemical bone formation markers versus bone resorption markers, which correlated with BMD changes. These findings suggest that abaloparatide may have therapeutic benefits in men with osteoporosis.

125I-labeled OP-1 is locally retained in a rabbit lumbar fusion model.

Osteogenic protein-1 is evolving as a potential bone graft alternative. Surgical site retention is important to maximize local osteoinduction and to limit peripheral effects. An established rabbit lumbar posterolateral fusion model was used to evaluate the systemic distribution and pharmacokinetics of locally applied osteogenic protein-1 delivered on a collagen carrier. L5-L6 intertransverse process fusions were performed on 27 New Zealand White rabbits. Radiolabeled (125)I-osteogenic protein-1 collagen putty was implanted. At intervals, whole blood, plasma, and excreta were analyzed for radioactivity with liquid scintillation counting. Surgical site and tissue radioactivity also were assessed by quantitative whole-body autoradioluminography of animals euthanized at times ranging from 6 hours to 35 days. Animals remaining at the final time were assessed for fusion with manual palpation, radiography, and histology. Limited distribution of radioactivity was observed in the blood, plasma, and tissues apart from at the surgical site and in the urinary bladder and thyroid. The mean residence time for osteogenic protein-1 collagen putty was 10.4 +/- 2.7 days. These excretion profiles and kinetic properties are similar to those described for recombinant human bone morphogenetic protein-2 in the rabbit model (mean residence times of 7.6 days and 10.2 days with different carriers).

In vivo BMP-7 (OP-1) enhancement of osteoporotic vertebral bodies in an ovine model.

BACKGROUND CONTEXT: Prevention of osteoporotic vertebral fractures could help at-risk individuals avoid the pain and morbidity associated with these fractures. Currently, patients with osteoporosis are treated with systemic medications to reduce fracture risk. Although effective, these therapies do not eliminate fractures and also tend to have a gradual time-dependent effect on fracture risk. The mechanism of action of the bone morphogenetic protein (BMP) family theoretically makes these molecules candidates for rapidly enhancing local bone structure. STUDY DESIGN: An in vivo study analyzing the effects of BMP-7 (osteogenic protein 1 [OP-1]) treatment on osteopenic ovine vertebral architecture and biomechanics. PURPOSE: We tested the hypothesis that local injection of OP-1 into osteopenic ovine vertebrae will improve bone mass and trabecular distribution, thereby reducing bone fragility and fracture risk. We specifically evaluated compressive biomechanics and morphology of osteopenic ovine vertebral bodies 6 months after local OP-1 treatment. STUDY DESIGN: In vivo animal study. METHODS: Skeletally mature sheep (n=24) underwent ovariectomy and were placed on low cation relative to anion diet. These interventions reduce bone density and induce skeletal fragility. After 6 months, sheep were randomly assigned to six treatment groups based on OP-1 dose (370 mg or 0 mg) and carrier with 4 animals/treatment group. Carriers A and B were poly-L-glycolic acid (PLGA) biospheres with different release kinetics (B allowing sustained BMP release); Carrier C was carboxymethylcellulose. After creating an 8-mm-diameter defect in the midvertebral body, sheep underwent intravertebral body implantation at two nonadjacent levels. Animals were euthanized 6 months after implantation and bone mineral density (BMD), biomechanics, and histomorphometry were assessed. Two-way analysis of variance was used to determine effects of OP-1 (alpha=0.05). RESULTS: An 81.9%, 333.2%, and 39.9% increase in stiffness was seen for OP-1 treated vertebra with Carriers A, B, and C respectively. Although these effects did not reach statistical significance, trends toward improvement were evident. Histology showed varied degrees of bony healing in the injection sites. Histomorphometrically, OP-1 treated vertebrae showed improvements in percent bone of up to 38% and star volume of up to 55% (with Carrier B). Improvements in whole vertebral body BMD were not detected for any treatment. CONCLUSION: In this study, local OP-1 treatment showed a positive trend in improving mechanical strength and histomorphometric parameters of osteopenic vertebra, despite the absence of consistent change in BMD. Controlled slow release of OP-1 using PLGA microspheres appeared to be the most effective method of protein delivery. In conclusion, we feel that the pilot data suggest that the use of OP-1 in the treatment of vertebral osteoporosis in an attempt to enhance bone strength merits further study.