Activin A and BMP chimera (AB204) induced bone fusion in osteoporotic spine using an ovariectomized rat model

Abstract

BACKGROUND CONTEXT: Recombinant human bone morphogenic protein 2 (rhBMP2) has been used to induce bone fusion in patients with spinal fusion surgery. However, the effectiveness of rhBMP2 in the bone fusion process is limited in osteoporosis patients, and a high dose of rhBMP2 for enough bone fusion sometimes provokes side effects. Therefore, substitutes for rhBMP2 with a higher therapeutic potency are needed, and already several studies have published the effectiveness of Activin A/BMP2 chimera (AB204) in new bone formation process in vitro and in vivo. PURPOSE: In the present study, we provide evidence that bone fusion activity of AB204 is superior to that of rhBMP2 in osteoporotic rat models. STUDY DESIGN/SETTINGS: An in vivo animal study was carried out. METHODS: A total of 40 Sprague-Dawley rats underwent bilateral ovariectomy. At 6 weeks after ovariectomy, a lumbar spinal bone fusion model of bilateral intertransverse process was performed. All rats were randomly divided into four groups as follows: rats receiving 5 µg of rhBMP2 (Group I), rats receiving 10 µg of rhBMP2 (Group II), rats receiving 5 µg of AB204 (Group III), and rats receiving 10 µg of AB204 (Group IV). Simple radiographs were performed at 6 and 12 weeks after bone fusion, and direct palpation, micro-CT, and immunohistochemistry (hematoxylin-eosin stain and Masson's trichrome stain) were performed at 12 weeks after bone fusion. The qualitative degree of bone fusion was assessed as manual fusion score from direct palpation, and radio-histologic fusion score from simple radiographs, micro-CT, and immunohistochemistry. Also, the quantitative degree of bone fusion was assessed using fusion bone volume by micro-CT and serum osteocalcin level as bone turnover markers. RESULTS: The change of body weight was not different among the groups during follow-up. The qualitative degree of bone fusion assessed by direct palpation, simple radiographs, micro-CT, and histologic evaluation was significantly different among the four groups. Also, the quantitative degree of bone fusion including fusion bone volume and serum osteocalcin was significantly different among the groups. Especially, in manual fusion score, radio-histologic fusion score, and fusion bone volume, the AB204 group revealed superior results to the rhBMP2 group when using the same dose. Furthermore, even the low-dose AB204 group (Group III) showed superior results to the high-dose rhBMP2 group (Group II) in radio-histologic fusion score and fusion bone volume. CONCLUSION: The effect of bone fusion in osteoporotic rats was significantly higher in the AB204 group than in the rhBMP2 group. CLINICAL SIGNIFICANCE: If further organized animal studies and clinical trials are provided, AB204 may be a good substitute for rhBMP2 in osteoporotic spinal fusion surgery, as a superior osteogenesis inducer. © 2019 Elsevier Inc.