Rationale

Delayed fracture healing and nonunion can present a challenging clinical scenario for the treating physician. Recombinant human bone morphogenetic protein‐2 ([rh]BMP‐2) is the most studied orthobiologic used to enhance fracture healing.

Clinical comment

While the majority of fractures heal uneventfully, it has been reported that 5–10% of fractures either fail to unite or demonstrate a delay in healing, and this risk varies depending on the bone involved (e.g. higher risk of delayed or nonunion in fractures of the tibia and proximal fifth metatarsal).¹ The concept of healing itself is also variably defined, as it can refer to radiographic healing (e.g. complete bridging at all cortices), clinical healing (e.g. no pain, return to activity), or a combination of the two. Therefore, alternative strategies designed to enhance fracture healing and to improve the treatment of delayed unions and nonunions are required. Growth factors, by virtue of their ability to regulate cell behavior, have been studied as a potential therapeutic to enhance fracture healing. The growth factors known to be expressed during fracture healing include BMPs, transforming growth factor (TGF) beta, fibroblast growth factor (FGF), and platelet derived growth factor (PDGF).^2–9 Bone morphogenetic proteins are members of the TGF‐β superfamily, and have been most extensively studied in the context of fracture healing.¹⁰ Bone morphogenetic proteins mediate their effect by binding to osteoprogenitor cells, thereby increasing the transcription of osteoinductive genes such as RUNX2 to enhance osteoblast differentiation.¹¹

Two different recombinant BMPs have been approved by the Food and Drug Administration (FDA) for clinical use in specific populations: (1) rhBMP‐2 (INFUSE^® Bone Graft, Medtronic), which may be used for acute open tibial shaft fractures in addition to standard fixation with intramedullary nail, or as an adjunct treatment to single‐level anterior interbody lumbar‐spinal fusion (L2–S1) in patients with degenerative disc disease, and (2) rhBMP‐7 (OP‐1 Putty, Stryker) which has received a humanitarian device exemption approval in tibial nonunion when an autograft is not allowed or has failed.¹² While both of these BMPs have been approved for clinical use, their testing and regulation have been different.

Available literature and quality of evidence

There are a number of high‐quality studies demonstrating the efficacy of rhBMP‐2 in enhancing fracture healing in animal models.^13–15 To date, there are three level I studies evaluating the efficacy of rhBMP‐2 in enhancing fracture healing in the setting of open tibial shaft fractures.

Findings

The first randomized controlled trial (RCT) to test the safety and efficacy of rhBMP‐2 was the BESTT (BMP‐2 Evaluation in Surgery for Tibial Trauma) trial.¹⁶ In this trial, Govender et al. randomized 450 patients with an open tibial shaft fracture to receive either standard of care (intramedullary nail and soft tissue management, n = 150) or the standard of care plus an implant containing rhBMP‐2/absorbable collagen sponge (0.75 mg/mL, n = 151 or 1.5 mg/mL, n = 149). The high‐dose rhBMP‐2 group (1.5 mg/mL) had significantly faster healing rates, lower infection rates (among Gustilo‐Anderson type IIIA and IIIB fractures), and a significant reduction in secondary interventions.¹⁶ At 12 months after surgery, 58% of the BMP‐2 group were “healed,” compared to 38% of the group treated with intramedullary nail alone (p = 0.001). The study defined healing as a combination of radiographic healing and meeting clinical criteria for healing. There were no significant differences in complications or adverse events between treatment groups. Based on the results of this study, the FDA granted premarket approval for rhBMP‐2 for the treatment of acute (within 14 days), open tibial shaft fractures. Following the publication of this study, other investigators noted the high proportion of patients in the control group that underwent unreamed intramedullary nailing compared to the study group.¹⁷ Reamed intramedullary nailing has been shown to have a possible benefit in the treatment of tibial shaft fractures, and was therefore likely a strong confounding variable in the BESTT trial results.¹⁸

Since the FDA approval of BMP‐2 for clinical use, several trials using BMP‐2 have had less‐promising results. In 2006, Swiontkowski et al. combined the data from the original BESTT trial with a second prospective RCT using the same methodology.¹⁹ The authors evaluated the use of rhBMP‐2 in open tibial shaft fractures in two separate subgroups: (1) 131 patients with Gustilo‐Anderson type 3A or 3B fractures and (2) 113 patients treated with reamed intramedullary nail.¹⁹ Within each subgroup, a comparison was made between those receiving rhBMP‐2 and controls who did not receive rhBMP‐2. In the first subgroup, the authors found that there was a significant improvement in the rhBMP‐2 groups, including fewer bone‐grafting procedures (p = 0.0005), fewer patients requiring secondary interventions (p = 0.0065), and a lower rate of infection (p = 0.0234) compared to the control group.¹⁹ In the second subgroup, there was no difference between those that received rhBMP‐2 and those that did not. The authors concluded that rhBMP‐2 significantly reduces the frequency of bone grafting in Gustilo‐Anderson type 3 fractures, but that this study was not originally designed for subgroup analysis, and therefore the data should be viewed with caution. In addition, the authors stated that, although rhBMP‐2 did not have any significant difference in patients that underwent reamed intramedullary nailing, there was a trend toward improvement in the rhBMP‐2 group, and therefore larger RCTs should be performed to answer this question.

In 2011, Aro et al. evaluated the efficacy of rhBMP‐2 in an RCT of 277 patients with open tibial shaft fractures treated with reamed intramedullary nailing.¹⁷ The authors found no significant difference in the rate of fracture healing or need for secondary procedures between treatment groups. Of note, there was a trend toward a higher rate of infection in the rhBMP‐2 group compared to the control group (19% vs 11%, p = 0.0645; difference in infection risk = 0.09; 95% confidence interva: 0.0 to 0.17). The authors concluded that the healing of open tibial shaft fractures treated with reamed intramedullary nailing was not significantly accelerated by the addition of rhBMP‐2. The trend toward an increased rate of infection differed from previous studies which demonstrated a possible decrease in infection rate with use of rhBMP‐2, and requires further study.

Another consideration with regards to the use of rhBMP‐2 is cost. The use of rhBMP‐2 may add anywhere from $5000 to $15 000 to the cost of treatment, depending on the amount of protein needed.²⁰ Proponents argue that these costs are offset by savings related to decreased operative time, lack of a bone grafting procedure, quicker hospital discharge, and faster return to work. There is limited evidence to support these claims, and a high risk of bias as the authors received financial support from the BMP manufacturing company.^21,22 A 2007 systematic review of RCTs did find that BMPs were associated with a reduced operating room time, improvement in clinical outcomes, and a shorter hospital stay as compared to autograft.²³ This study evaluated both rhBMP‐2 and rhBMP‐7, and included acute tibial fractures, nonunions, and spinal procedures. The true cost efficacy of BMP is probably not known at this time. There is a need for more rigorous cost‐effectiveness analysis related to the use of BMP.

Resolution of clinical scenario

• rhBMP‐2 may assist with the healing of open tibial fractures treated with unreamed nails, but it has shown no effect when reamed intramedullary nailing is performed.
  
• There is conflicting evidence that BMP improves infection rates.
  
• The high cost and safety concerns for the use of rhBMP‐2 currently limit its utility as a therapeutic in the treatment of open tibial shaft fractures.
  
• Further research aimed at increasing the clinical efficacy of rhBMP‐2, while decreasing the risk of side effects and reducing overall cost, may improve the therapeutic potential of this growth factor.

Rationale

Delayed fracture healing and nonunion is commonly treated with autologous bone grafting, which has been shown to enhance fracture healing. Given the increased risk of complications and donor site morbidity with harvesting autograft bone, several studies have evaluated the efficacy of using BMP in treating nonunions.

Clinical comment

Fracture nonunion is a challenging clinical scenario, and the cause of delayed healing is frequently multifactorial. To enhance fracture healing, autologous bone grafting has traditionally been used, as it not only provides structural support but also contains osteoinductive and osteogenic factors to assist with healing. The major drawback of autologous bone grafting is the donor site morbidity.^24,25 Therefore, several investigators have evaluated the efficacy of BMP in enhancing fracture healing for long‐bone nonunions.

Bone morphogenetic protein‐7, also known as osteogenic protein‐1 (OP‐1), is a member of the TFG‐β superfamily that has been shown to be involved in fracture healing in experimental models. This molecule demonstrates an increased expression during endochondral ossification, and has been shown to strongly induce osteoblastic differentiation.^6,26

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