Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) for the Treatment of Nonunion of the Femur in Children and Adolescents: A Retrospective Analysis.

Background. The aim of this study was to examine clinical and radiographic healing after rhBMP-2 application in children and adolescents presenting with nonunion of the femur and to investigate the safety of rhBMP-2 use in these cases. Materials and Methods. We reviewed the medical records of five patients with a mean age of 11 years (5.4 to 16.2) with nonunion of the femur who were treated with rhBMP-2 and internal fixation using a locking plate at a single institution. Particular attention was paid to identify all adverse events that may be due to rhBMP-2 use. Results. Union occurred in four of five patients at a mean of 12.1 months (7.9 to 18.9). The locking plates were removed after a mean of 16 months (11 to 23). One patient had nonunion due to deep infection. After a mean follow-up of 62.5 months (17 to 100), union was still evident in all four patients and they were fully weight-bearing without pain. Discussion. In this retrospective study, rhBMP-2 combined with a locking plate has been used successfully to treat children and adolescents with nonunion of the femur in four of five cases. One major complication was thought to be possibly related to its use.

Bone morphogenetic protein-2 for the treatment of congenital pseudarthrosis of the tibia or persistent tibial nonunion in children and adolescents: A retrospective study with a minimum 2-year follow-up.

There is a lack of studies reporting on rhBMP-2 application in pediatric orthopaedics, although few reports demonstrated promising results of the use of rhBMP-2 in children, especially for spine fusion and for the treatment of congenital pseudarthrosis of the tibia. The objectives of this study were (1) to examine clinical and radiographic healing after rhBMP-2 application for the treatment of congenital pseudarthrosis of the tibia (CPT) or persistent tibial nonunion in children and adolescents, and (2) to investigate the safety of rhBMP-2 use in these cases. Therefore we reviewed the medical records of ten patients with a mean age of 8.6 years (2.3-21) with CPT (n = 7) or persistent tibial nonunion for at least six months (n = 3) who had been treated with rhBMP-2. Nine of ten patients had union at final follow-up, after a mean of 72.9 months (25-127). In the CPT group, primary healing of the pseudarthrosis occurred in six of seven patients at a mean of 5.2 months (3-12). Repeat rhBMP-2 application was performed in three patients; two patients had one additional application each, and one patient had three additional applications. Complications that may be attributed to the use of rhBMP-2 were seen in two of fifteen applications, including a compartmemt syndrome and a hematoma. In this retrospective case series rhBMP-2 has been used successfully to treat CPT or persistent tibial nonunion in pediatric patients. However, prospective randomized controlled trials are warranted to investigate the long-term efficacy and safety of rhBMP-2 use in these cases.

Evaluation of complications associated with off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in pediatric orthopaedics.

The off-label use of recombinant human bone morphogenetic protein-2 to promote bone healing in adults has significantly increased in recent years, while reports of recombinant human bone morphogenetic protein-2 application in children and adolescents are very rare. The aim of this study was to evaluate the safety of single and repetitive recombinant human bone morphogenetic protein-2 use in pediatric orthoapedics. Therefore we reviewed the medical records of 39 patients who had been treated with recombinant human bone morphogenetic protein-2 at our institution. Their mean age was 10.9 years. Recombinant human bone morphogenetic protein-2 was used in 17 patients for spine fusion, in 11 patients for the treatment of congenital pseudarthrosis of the tibia or tibial nonunion, in 5 patients for the management of femoral nonunion, in 5 patients for nonunions at other locations, and in 1 case for tibial shortening. Special attention was paid to identify all adverse events that may be attributed to recombinant human bone morphogenetic protein-2 use, including local inflammatory reactions, allergic reactions, systemic toxicity, excessive wound swelling, hematoma, compartment syndrome, infection, heterotopic ossification, excessive bone growth, carcinogenicity, and the consequences of repeated applications of recombinant human bone morphogenetic protein-2. Follow-up was a mean of 39 months. Forty-six operations with application of rhBMP-2 were performed. Complications that may be due to application of recombinant human bone morphogenetic protein-2 were seen after 18 operations including swelling, increase in temperature, wound secretion, redness and hyperthermia. We consider the three cases of necessary revisions, one due to hematoma, one due to development of a compartment syndrome, and one due to deep infection, to be the only complications related to the use of recombinant human bone morphogenetic protein-2. In conclusion, we found few complications attributable to application of recombinant human bone morphogenetic protein-2 in pediatric patients.

Low turnover osteoporosis in sheep induced by hypothalamic-pituitary disconnection.

The hypothalamus is of critical importance in regulating bone remodeling. This is underscored by the fact that intracerebroventricular-application of leptin in ewe leads to osteopenia. As a large animal model of osteoporosis, this approach has some limitations, such as high technical expenditure and running costs. Therefore we asked if a surgical ablation of the leptin signaling axis would have the same effects and would thereby be a more useful model. We analyzed the bone phenotype of ewe after surgical hypothalamo-pituitary disconnection (HPD + OVX) as compared to control ewe (OVX) after 3 and 12 months. Analyses included histomorphometric characterization, micro-CT and measurement of bone turnover parameters. Already 3 months after HPD we found osteopenic ewe with a significantly decreased bone formation (69%) and osteoclast activity (49%). After a period of 12 months the HPD group additionally developed an (preclinical) osteoporosis with significant reduction (33%) of femoral cortical thickness, as compared to controls (OVX). Taken together, HPD leads after 12 month to osteoporosis with a reduction in both trabecular and cortical bone caused by a low bone turnover situation, with reduced osteoblast and osteoclast activity, as compared to controls (OVX). The HPD-sheep is a suitable large animal model of osteoporosis. Furthermore our results indicate that an intact hypothalamo-pituitary axis is required for activation of bone turnover.