Off-Label use of rhBMP-2/rhBMP-7 successfully treats congenital tibialpseudarthrosis in children
by
Gabriela Voskerician, PhD
Congenital pseudarthrosis of the tibia (CPT) describes a nonunion of a tibial fracture that develops spontaneously or after a minor trauma. It is a bone fracture that fails to heal on its own. Although CPT is known to develop within the first two years of life, there have been reported cases of development before birth as well as later in life. Professor Spiro and his colleagues from University Medical Center Hamburg-Eppendorf report on the off-label success of using rhBMP-2/rhBMP-7 in the treatment of congenital tibialpseudarthrosis in children ( Scientists and physicians have fought an uphill battle to identify a treatment for this highly vulnerable population, currently with no regulatory success specific to this pediatric indication. Through sustained efforts using prospective and retrospective clinical trial outcomes and analyses, and building community awareness through reports such as this one, the authors hope that diligent efficacy demonstration in independent case studies will drive regulatory entities’ attention to the benefits ofrhBMP-2/rhBMP-7 for pediatric use.
With more than 20 different bone morphogenetic proteins (BMPs) with the capacity to induce ectopic bone formation, it is intriguing to ask why only two derivatives,rhBMP-2 and rhBMP-7, have actually made it through the regulatory approval process for use in adult patients.. No “conspiracy theory” should be implied, but these two recombinant proteins have shown proven efficacy in inducing mesenchymal cell differentiation, proliferationand maturation into osteoblasts, and improving the healing process. Other BMPs also demonstrate an extraordinary role in fracture healing and new bone formation, but they are currently at various stages of laboratory and pre-clinical evaluation.
Complications associated with the use of rhBMP-2 and rhBMP-7 in pediatric patients have been reported, providing a critical tipping point against their current off-label use. Professor Spiro discloses that the Food and Drug Administration (FDA) has restricted the use of rhBMP-2 to address safety concerns related to skeletal immaturity and surgical procedure challenges. Especially related to the latter, Professor Spiro emphasizes the concern related to excessive wound swelling, hematoma, wound breakdown, erythema, infection, neurologic compromise, acute compartment syndrome, excessive bone growth, systemic toxicity and carcinogenicity. Specific to children, the main concerns regarding the use of rhBMP-2 may be the unknown effects of this protein on the local growth plate and long-term carcinogenicity. However, in recognizing the potential of rhBMP-2use in pediatric patients, the FDA permits off-label use if supported by informed consent of risk. Through this approach, the FDA had already recognized that CPT represents one of the most challenging pathologies in pediatric orthopaedics, and that the benefits of using rhBMP-2 in these difficult cases may outweigh the risks.
To showcase the risk of undertaking such complex cases, Professor Spiro and his colleagues report on a CPT patient who was subjected to 28 previous surgical procedures including resection of the pseudarthrosis, intramedullary fixation, bone grafting and Ilizarov fixation, all failing to induce fracture union. Following a single rhBMP-2 treatment, fracture union was achieved, and, at follow-up, found to be persistent.
I would like to thank Professor Spiro and his colleagues for kindly agreeing to offer a cohesive clinical and
investigational account of their ongoing work on the importance of rhBMP-2 and rhBMP-7 in children and adolescents.
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