BACKGROUND: Although clinical bone morphogenetic protein (BMP) therapy is effective at enhancing bone formation in patients managed with spinal arthrodesis, the required doses are very high. Teriparatide (parathyroid hormone 1-34) is approved by the U.S. Food and Drug Administration to treat osteoporosis and is a potent anabolic agent. In this study, intermittent administration of parathyroid hormone 1-34 combined with transplantation of BMP was performed to elucidate the effect of parathyroid hormone 1-34 on the fusion rate and quality of newly formed bone in a rat model. METHODS: A total of forty-eight male Sprague-Dawley rats underwent posterolateral lumbar spinal arthrodesis with one of three different treatments with recombinant human (rh) BMP-2: (1) 0 μg (control), (2) 2 μg (low dose), or (3) 50 μg (high dose). Each of the rhBMP-2 treatments was studied in combination with intermittent injections of either parathyroid hormone 1-34 (180 μg/kg/wk) or saline solution starting two weeks before the operation and continuing until six weeks after the operation. Osseous fusion was assessed with use of radiographs and a manual palpation test. Microstructural indices of the newly formed bone were evaluated with use of micro-computed tomography. The serum markers of bone metabolism were also quantified. RESULTS: The fusion rate in the group treated with 2 μg of rhBMP-2 significantly increased (from 57% to 100%) with the administration of parathyroid hormone 1-34 (p < 0.05). The fusion rates in the other groups did not change significantly with the administration of parathyroid hormone 1-34. The bone volume density of the newly formed bone significantly increased in both the 2-μg and 50-μg rhBMP-2 treatment groups with the administration of parathyroid hormone 1-34 (p < 0.01). Micro-computed tomography scans of the newly formed bone clearly demonstrated an abundance of trabecular bone formation in the group treated with parathyroid hormone 1-34. In addition, serum levels of osteocalcin were significantly increased in the parathyroid hormone 1-34 treatment group. CONCLUSIONS: Intermittent administration of parathyroid hormone 1-34 significantly increased fusion rates in the group treated with low-dose rhBMP-2, and it improved the quality of the newly formed bone in both the high and low-dose groups in a rat model of rhBMP-2-induced spinal fusion. CLINICAL RELEVANCE: Our results suggest that the combined administration of rhBMP-2 and parathyroid hormone 1-34 may lead to efficient bone regeneration.
BACKGROUND: Although clinical bone morphogenetic protein (BMP) therapy is effective at enhancing bone formation in patients managed with spinal arthrodesis, the required doses are very high. Teriparatide (parathyroid hormone 1-34) is approved by the U.S. Food and Drug Administration to treat osteoporosis and is a potent anabolic agent. In this study, intermittent administration of parathyroid hormone 1-34 combined with transplantation of BMP was performed to elucidate the effect of parathyroid hormone 1-34 on the fusion rate and quality of newly formed bone in a rat model. METHODS: A total of forty-eight male Sprague-Dawley rats underwent posterolateral lumbar spinal arthrodesis with one of three different treatments with recombinant human (rh) BMP-2: (1) 0 μg (control), (2) 2 μg (low dose), or (3) 50 μg (high dose). Each of the rhBMP-2 treatments was studied in combination with intermittent injections of either parathyroid hormone 1-34 (180 μg/kg/wk) or saline solution starting two weeks before the operation and continuing until six weeks after the operation. Osseous fusion was assessed with use of radiographs and a manual palpation test. Microstructural indices of the newly formed bone were evaluated with use of micro-computed tomography. The serum markers of bone metabolism were also quantified. RESULTS: The fusion rate in the group treated with 2 μg of rhBMP-2 significantly increased (from 57% to 100%) with the administration of parathyroid hormone 1-34 (p < 0.05). The fusion rates in the other groups did not change significantly with the administration of parathyroid hormone 1-34. The bone volume density of the newly formed bone significantly increased in both the 2-μg and 50-μg rhBMP-2 treatment groups with the administration of parathyroid hormone 1-34 (p < 0.01). Micro-computed tomography scans of the newly formed bone clearly demonstrated an abundance of trabecular bone formation in the group treated with parathyroid hormone 1-34. In addition, serum levels of osteocalcin were significantly increased in the parathyroid hormone 1-34 treatment group. CONCLUSIONS: Intermittent administration of parathyroid hormone 1-34 significantly increased fusion rates in the group treated with low-dose rhBMP-2, and it improved the quality of the newly formed bone in both the high and low-dose groups in a rat model of rhBMP-2-induced spinal fusion. CLINICAL RELEVANCE: Our results suggest that the combined administration of rhBMP-2 and parathyroid hormone 1-34 may lead to efficient bone regeneration.
Authors: Hsin Chuan Pan; Soonchul Lee; Kang Ting; Jia Shen; Chenchao Wang; Alan Nguyen; Emily A Berthiaume; Janette N Zara; A Simon Turner; Howard B Seim; Jin Hee Kwak; Xinli Zhang; Chia Soo Journal: Am J Pathol Date: 2017-05-11 Impact factor: 4.307