Estrogen-Dependent Actions of Bone Morphogenetic Protein-7 on Spine Fusion in Rats

Department of Orthopaedic Surgery, University of California, Davis, Davis, California, United States
Spine (Impact Factor: 2.3). 09/2005; 30(15):1706-11. DOI: 10.1097/01.brs.0000172230.01655.55
Source: PubMed

ABSTRACT Intertransverse process spinal fusion using recombinant human bone morphogenetic protein-7 (rhBMP-7) was performed in intact and ovariectomized female rats.
To examine fusion rates in intact and ovariectomized female rats using rhBMP-7 to determine if spine fusion is dependent on estrogen status.
Rat spinal fusion has been established as a consistent, efficient model for posterolateral intertransverse process fusion. Previous experiments have confirmed the efficacy of pellets containing the carrier, insoluble collagen bone matrix (ICBM), and rhBMP-7 to augment intertransverse process single level fusion in a rat model. Studying these implications in an osteoporosis model is of clinical value because there are many patients undergoing spinal fusion surgery that have osteoporotic bone disease, and there is a steady increase in this group of patients.
A total of 15 ovariectomized and 15 intact Sprague-Dawley female rats were randomly assigned to groups receiving 25 mg ICBM alone, 25 mg ICBM + 10 microg rhBMP-7, and 25 mg ICBM + 30 microg rhBMP-7. Spinal fusion was evaluated by manual motion testing at each lumbar segment, radiographic evaluation using the Lenke grading system, and histology.
Ovariectomized and intact rats receiving 25 mg carrier ICBM alone did not show spinal fusion. With 25 mg ICBM + 10 microg rhBMP-7, there was not a significant difference in fusion rates between intact and ovariectomized rats (P = 0.63). Ovariectomized rats receiving 25 mg ICBM + 30 microg rhBMP-7 showed significantly lower fusion rates than intact rats (P = 0.013).
These data suggest that spinal fusion using rhBMP-7 is estrogen-dependent in rats. At the dosages used, rhBMP-7 was unable to overcome the inhibitory effects of estrogen deficiency on spinal fusion.

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    • "Low bone mass and micro-architectural deterioration of osteoporotic bone structure leads to bone fragility and increased susceptibility to fractures, the healing of which is often biomechanically impaired.[1] Indeed, a lack of oestrogen has been shown to retard bone formation in studies of spinal fusion or fracture in an osteoporotic rat model.[23] The ability to enhance the healing process in osteoporotic fractures is desirable, particularly in view of the frequent failure of metallic instrumentation in fragile osteoporotic bones.[45] "
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    ABSTRACT: Osteoporosis is characterized by low bone mass, bone fragility and increased susceptibility to fracture. Fracture healing in osteoporosis is delayed and rates of implant failure are high with few biological treatment options available. This study aimed to determine whether a single dose of bone morphogenetic protein-7 (BMP-7) in a collagen/carboxy-methyl cellulose (CMC) composite enhanced fracture healing in an osteoporotic rat model. An open femoral midshaft osteotomy was performed in female rats 3 months post-ovarectomy. Rats were randomized to receive either BMP-7 composite (n = 30) or composite alone (n = 30) at the fracture site during surgery. Thereafter calluses were collected on days 12, 20 and 31. Callus cross-sectional area, bone mineral density, biomechanical stiffness and maximum torque, radiographic bony union and histological callus maturity were evaluated at each time point. There were statistically significant increases in bone mineral density and callus cross-section area at all time points in the BMP-7 group as compared to controls and biomechanical readings showed stronger bones at day 31 in the BMP-7 group. Histological and radiographic evaluation indicated significant acceleration of bony union in the BMP-7 group as compared to controls. This study demonstrated that BMP-7 accelerates fracture healing in an oestrogen-deficient environment in a rat femoral fracture healing model to scientific relevance level I. The use of BMP-7 composite could offer orthopedic surgeons an advantage over oestrogen therapy, enhancing osteoporotic fracture healing with a single, locally applied dose at the time of surgery, potentially overcoming delays in healing caused by the osteoporotic state.
    Indian Journal of Orthopaedics 11/2013; 47(6):540-6. DOI:10.4103/0019-5413.121569 · 0.64 Impact Factor
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    • "Osteoporotic bones are characterised by bone fragility with diminished bone density, micro-architectural deterioration, increased frequency of fracture and a retarded fracture healing process. A lack of estrogen has been shown to retard bone healing in several animal studies of spinal fusion and long bone fracture (Namkung-Matthai et al. 2001; Moazzaz et al. 2005). Hormone replacement therapy (HRT) could improve fracture healing, but because of potential side effects of HRT, alternatives to enhance osteoporotic fracture healing are eagerly sought. "
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    ABSTRACT: In postmenopausal women, estrogen withdrawal results in decrease in bone density or osteoporosis. Osteoporosis leads to fracture and retards bone-healing response. Bone morphogenetic protein-7 (BMP-7), a member of the transforming-growth factor-beta superfamily, has been shown as a promising candidate that stimulates bone growth in its application to fracture healing. The purpose of this study was to determine whether BMP-7 could enhance bone formation in the absence of estrogen. Female rats underwent a controlled closed fracture at the midshaft of the right femur. The callus tissues were harvested from the fracture site eight days following the fracture, and were cultured in serum-free media. The explanted callus tissues were then treated with BMP-7, estrogen (E2) or both. We assessed bone formation by measuring alkaline phosphatase (AP) activity, expression of an osteogenic transcription factor, Runt-related transcription factor-2 (Runx2), production of nitric oxide (NO), and calcium mineralization. Supplementation of serum-free cultures with BMP-7 alone increased cell proliferation by twofold, caused a 6.5-fold increase in AP activity, and enhanced calcium mineralization after 48 h. Moreover, BMP-7 in combination with E2 caused a 8.2-fold increase in the AP activity. Runx2 protein expression was increased following stimulation with BMP-7 and E2. Interestingly, E2 induced the amount of NO production by twofold, whereas BMP-7 did not, either alone or with E2. Thus, BMP-7 could enhance early and late markers of bone fracture healing in callus explant cultures, except for NO. BMP-7 could be a promising growth factor in the treatment of fractures as a consequence of osteoporosis.
    The Tohoku Journal of Experimental Medicine 01/2010; 221(1):61-8. DOI:10.1620/tjem.221.61 · 1.35 Impact Factor
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    ABSTRACT: We are now entering an exciting new era in spinal surgery where the inherent osteoinductive capacity of the body has been harnessed for bone formation for therapeutic purposes. Recombinant bone morphogenetic proteins have been extensively studied in both the pre-clinical and clinical arena for spinal fusion with considerable success. The challenges facing spine surgeons now is the development of site-specific carriers and optimal doses for these growth factors. This review highlights the recent advances in this regard.
    Cytokine & Growth Factor Reviews 07/2005; 16(3):347-55. DOI:10.1016/j.cytogfr.2005.02.004 · 5.36 Impact Factor
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