A DOSE-FINDING STUDY OF rhBMP-2/ABSORBABLE COLLAGEN SPONGE (ACS) IN OPEN TIBIAL SHAFT FRACTURES REQUIRING SURGICAL MANAGEMENT

Participants: D. Hak, J. Goulet, M.L. Greenfield, A. Clotfelter

Keywords: bone morphogenetic protein, bone graft substitute, open tibial shaft fractures

Introduction

Bone has significant capacity for regeneration and healing. However, surgeons are often presented with osseous defects that will not heal properly without bone graft or other implanted materials. These defects may be caused by orthopaedic trauma, disease, developmental deformity, or tumor resection. Orthopaedic, plastic, and oral surgeons perform more than 250,000 bone grafts annually in the United States (Muschler, 1992, Grazier, 1984, In Vivo, 1992).

Various bone grafting materials are used with different degrees of success. These materials include autogenous bone (commonly harvested from the patient’s iliac crest), allogeneic bone, bone graft substitutes (e.g., tricalcium phosphate and porous hydroxyapatite), or a combination of these materials. Autologous graft is currently the most successful of grafts due to its ability to stimulate new bone formation. It is limited, however, by the amount of bone that can be removed from a secondary site. Additionally, there are risks associated with harvesting the bone. Allogeneic bone and synthetic implants are limited by the fact that they are merely osteoconductive rather than osteoinductive. Allogeneic bone also carries the risk of potential adventitious agent transmission.

Additionally, many patients with fractures or other osseous defects, which do not require bone grafting, may benefit from accelerated healing. This may result in fewer complications and lower treatment costs. Improved treatment methods may not only replace bone graft, but may also speed bone healing.

Bone morphogenetic proteins (BMPs), which belong to the Transforming Growth Factor-ß superfamily, offer potential for treating osseous defects. They have been shown to induce bone formation in various preclinical models (Urist, 1965, Sampath, 1981, Gerhart, 1993, Toriumi, 1991). The osteoinductive capacity of a BMP is expected to allow it to be used clinically to enhance regeneration of bone in cases that would normally require bone grafting. The use of such an osteoinductive protein, along with an appropriate carrier, may improve the ability of the bone inducing material to integrate into the surrounding bone and improve healing. The use of BMPs is not expected to be limited by anatomic site; that is, BMPs may be effective in many indications such as maxillofacial reconstruction and alveolar ridge augmentation, trauma, repair of nonunion fractures, avascular necrosis, or spinal fusion.

The high rate of delayed union associated with standard treatment provides an opportunity to evaluate the efficacy of rhBMP-2/ACS in an indication for which there is genuine medical need for improved outcomes.

The primary objectives of this study are to (1) evaluate the safety of rhBMP-2/ACS, when used in the treatment of open tibial shaft fractures, (2) identify the optimal rhBMP-2 dose that will prevent a delayed union based on clinical and radiographic assessment of fracture healing, (3) assess the time to radiographic fracture union, and (4) evaluate the potential economic benefit of treatment with reBMP-2/ACS.

Materials and Methods

This is a multicenter, prospective, single-masked, stratified, randomized controlled study. The study population includes patients who have acute open fractures of the tibia that are treated with intramedullary nailing. Each enrolled patient will undergo the standard surgical treatment of the fractured tibia and open wound. As an adjuvant to standard treatment, patients assigned to the rhBMP-2/ACS treatment groups will also receive rhBMP-2/ACS in one of two concentrations (0.75 mg/mL or 1.5 mg/mL) at the time of definitive wound closure. All patients will be followed for a total of 12 months following definitive wound closure.

Progress

60 patients from all sites have been enrolled. 6 patients are from the University of Michigan. All study patients have completed one year follow up and their data are currently being analyzed.