Local Administration of Ibandronate and Bone Morphogenetic Protein-2 After Ischemic Osteonecrosis of the Immature Femoral Head A Combined Therapy That Stimulates Bone Formation and Decreases Femoral Head Deformity

Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, 2222 Welborn Street, Dallas, TX 75219, USA.
The Journal of Bone and Joint Surgery (Impact Factor: 5.28). 05/2011; 93(10):905-13. DOI: 10.2106/JBJS.J.00716
Source: PubMed


Bisphosphonate therapy has been shown to preserve the osteonecrotic femoral head in experimental and short-term clinical studies. However, a lack of new bone formation within the preserved femoral head due to the inhibition of bone remodeling is a concern. The purpose of this investigation was to determine if combined therapy consisting of ibandronate and bone morphogenetic protein-2 (BMP-2) can preserve the shape of the femoral head and stimulate new bone formation in an immature animal model of ischemic osteonecrosis.
Ischemic osteonecrosis was surgically induced in immature pigs. Four groups were studied: normal, treated with saline solution, treated with ibandronate, and treated with both ibandronate and BMP-2 (the ibandronate + BMP-2 group). The animals were killed eight weeks after surgery. Radiographic, histological, and histomorphometric assessments were performed.
Radiographic assessment showed better preservation of the femoral head shape-i.e., a 54% (CI [95% confidence interval]: 22%, 86%) higher mean epiphyseal quotient-in the ibandronate + BMP-2 group than in the saline group. Histological assessment showed increased trabecular bone in the ibandronate + BMP-2 group as compared with that in the saline group. The mean values for trabecular bone volume, thickness, and number and for osteoblast surface were an average of 400% (CI: 242%, 558%), 212% (CI: 166%, 259%), 71% (CI: 6%, 137%), and 2402% (CI: 2113%, 2693%) higher, respectively, in the ibandronate + BMP-2 group than in the saline group. The osteoclast number was significantly reduced in the ibandronate + BMP-2 group compared with that in the saline group (-59% [CI: -75%, -42%]). The mean osteoblast surface value in the ibandronate + BMP-2 group was significantly higher (2567% [CI: 2258%, 2877%]) than that in the ibandronate group. Heterotopic ossifications were present in the capsule of the hip joint in the ibandronate + BMP-2 group.
A combination of ibandronate and BMP-2 decreased femoral head deformity while stimulating bone formation in an immature animal model of ischemic osteonecrosis.

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    • "As reported by Vandermeer et al. [29], concurrent implantation of diphosphate and rhBMP-2 achieved an optimal outcome for the repair of the necrotized femoral head in animals. This observation indicated that a concurrent implementation of suppression to osteolysis and promotion to ossification might facilitate a better necrotized bone repair. "
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    ABSTRACT: The purpose of this study was to compare the clinical outcomes of impacted bone graft with or without recombinant human bone morphogenetic protein-2 (rhBMP-2) for osteonecrosis of the femoral head (ONFH). We examined the effect of bone-grafting through a window at the femoral head-neck junction, known as the "light bulb" approach, for the treatment of ONFH with a combination of artificial bone (Novobone) mixed with or without rhBMP-2. A total of 42 patients (72 hips) were followed-up from 5 to 7.67 years (average of 6.1 years). The patients with and without BMP were the first group (IBG+rhBMP-2) and the second group (IBG), respectively. The clinical effectiveness was evaluated by Harris hip score (HHS). The radiographic follow-up was evaluated by pre-and postoperative X-ray and CT scan. Excellent, good, and fair functions were obtained in 36, 12, and 7 hips, respectively. The survival rate was 81.8% and 71.8% in the first and second group, respectively. However, the survival rate was 90.3% in ARCO stage IIb, c, and only 34.6% in ARCO stage IIIa(P<0.05). It was concluded that good and excellent mid-term follow-up could be achieved in selected patients with ONFH treated with impacted bone graft operation. The rhBMP-2 might improve the clinical efficacy and quality of bone repair.
    PLoS ONE 06/2014; 9(6):e100424. DOI:10.1371/journal.pone.0100424 · 3.23 Impact Factor
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    • "It is often occurs when the blood supply to bone is disrupted. Bisphosphonate therapy has been shown to preserve the AVN of femoral head in experimental and short-term clinical studies [26]. Increased oxidative stress is considered one of the main causes of steroid-induced AVN of the femoral head [27]. "
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    ABSTRACT: Background A meta-analysis was performed to assess the association between healing rate, avascular necrosis (AVN) of femoral head and two reductions-open reduction internal fixation (ORIF) and closed reduction internal fixation (CRIF) for femoral neck fracture. Methods A literature-based search was conducted to identify all relevant studies published before September 10, 2013. The odd ratio (OR) and 95% confidence interval (CI) were used for estimating the effects of the two reduction methods. Data were independently extracted by two investigators who reached a consensus on all of the items. The heterogeneity between studies was examined by χ2-based Q statistic. Egger’s regression analysis was used to evaluate publication bias. Statistical analysis was performed by Stata 10.0 software. Results We examined 14 publications. The results of the present meta-analysis showed that AVN of femoral head were significant associated with the two reductions (CRIF vs. ORIF, OR = 1.746, 95% CI 1.159-2.628, p = 0.008), while the healing rate were not (CRIF vs. ORIF, OR = 0.853, 95% CI 0.573-1.270, p = 0.433). Conclusion The present meta-analysis indicated the risk of AVN of femoral head was significant higher after CRIF fixation compared with ORIF, but no association between the healing rate and the two reductions for femoral neck fracture.
    BMC Musculoskeletal Disorders 05/2014; 15(1):167. DOI:10.1186/1471-2474-15-167 · 1.72 Impact Factor
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    • "angiogenesis and new bone formation). Moreover, we have shown that the treatment of piglet ischemic osteonecrosis with BMP2 via local injection increased new bone formation as well as revascularization during bone healing process [5], suggesting an important role of BMP2 in bone-recovery following ischemic osteonecrosis. We postulated that BMP2 upregulation shortly after ischemic osteonecrosis may initiate the early angiogenic response involved in the repair process. "
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    ABSTRACT: Juvenile ischemic osteonecrosis of the femoral head (IOFH) is one of the most serious hip conditions causing the femoral head deformity. Little is known about BMP signaling following ischemic osteonecrosis. In this study, we found acute BMP2 upregulation in the femoral head cartilage 24 hours after ischemic induction using our immature pig IOFH model. Similarly, in our ischemic osteonecrosis mouse model, BMP2 expression and BMP signaling were enhanced in the articular cartilage surrounding the necrotic bone. BMP2 was increased in cartilage explants and primary chondrocytes under hypoxia (1% O(2)) compared with normoxia (21% O(2)). Addition of the hypoxia inducible factor 1 (HIF1) activator DFO significantly increased BMP2 while HIF1 silencing (siHIF1) only partially reduced BMP2, suggesting other mechanisms of BMP2 upregulation being present. Hypoxia is known to induce the production of free oxygen radicals, which are converted to hydrogen peroxide (H(2)O(2)) by superoxide dismutase 2 (SOD2). As an alternative mechanism, we investigated the effect of H(2)O(2)/ SOD2 production on BMP2 upregulation. Chondrocytes produced more H(2)O(2) under hypoxia than normoxia. H(2)O(2) addition to the chondrocyte culture also significantly increased BMP2 expression. SOD2 was also dramatically increased in the ischemic pig cartilage at 24 hours following surgery and in primary chondrocytes/cartilage explants culture under hypoxia. SOD2 protein addition to the chondrocyte culture significantly increased BMP2. Moreover, DFO significantly increased SOD2 while HIF1 silencing only partially reduced SOD2. These results suggest that the acute BMP2 response of chondrocytes to ischemic osteonecrosis is more dominantly through the H(2)O(2) production and only partly through the HIF1 pathway.
    Bone 12/2012; 53(1). DOI:10.1016/j.bone.2012.11.023 · 3.97 Impact Factor
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