Preliminary experience with the combined use of recombinant bone morphogenetic protein and bisphosphonates in the treatment of congenital pseudarthrosis of the tibia

Abstract

Purpose Congenital pseudarthrosis of the tibia (CPT) is a rare but serious disorder in children. No single approach has clearly emerged as superior in terms of operative procedure, fixation, optimal time for surgery or adjunctive pharmaceutical intervention. CPT is frequently associated with neurofibromatosis type 1 (NF1), a condition featuring deficient bone anabolism and excessive catabolism. We have therefore combined the use of bone morphogenetic proteins (BMP) with bisphosphonates (BP) as an adjunct to surgical intervention. Methods Between 2002 and 2008 we administered BMP-7 (OP-1) at the time of surgery followed by BP (pamidronate or zoledronic acid) in eight Crawford type IV CPT cases in seven patients (six with a confirmed diagnosis of NF1) with a median age of 7 years (range 2 years 11 months to 12 years) at surgery. Results In six of eight cases, this approach led to primary healing after a mean of 5.5 months (range 4–7 months). One of these cases represented 17 months after primary healing of a proximal CPT with a new further distal fracture that required multiple operations to finally unite at 19 months. The two remaining cases ultimately reached union after multiple operations at 14 and 30 months, respectively, but required recent treatment for refractures. Conclusion Based on these clinical data (primary healing in 6/8 cases) and prior pre-clinical findings, we propose that BP therapy may be helpful in preserving the BMP-induced bone formation by inhibiting the osteoclastic bone loss. Key factors to achieve union in CPT include sufficient fixation, meticulous resection of the dysplastic tissue and the establishment of a net anabolic environment for bone healing. Whether our biological concept of balancing the anabolic and catabolic responses with BMP and BP improves healing rates in the complex treatment of NF1 CPT remains uncertain and warrants larger prospective multicentre trials.