Biologics in Fracture Care

Abstract

Delayed healing and nonunion remain significant clinical issues in fracture care. The field of biologic augmentation (orthobiologics) has been developed to help solve this problem. Orthobiologics rely on the core principles of osteoinduction, osteogenesis, and osteoconduction. The gold standard remains autograft in that it demonstrates all three of these properties and has been shown in numerous studies to aid in fracture union. However, the use of autograft is limited by quantity available, and there are problems with donor site morbidity. For this reason, techniques such cell-based therapy, use of synthetic bone void fillers, and use of growth factors such as bone morphogenic protein (BMP) have been developed. This chapter will review the clinical evidence for use of these techniques and materials in fracture care. The discussion on cell-based therapy to deliver progenitor cells to the site of injury will mainly focus on bone marrow aspirate (BMA), as this is the most commonly used strategy in clinical practice. We will investigate the evidence for BMA use as a percutaneous injection into a site of nonunion or as an augmentation of graft products during revision fixation for nonunion. We will also discuss the use of synthetic bone void fillers including calcium phosphate and calcium sulfate.

Keywords

Autograft, BMP, Bone marrow aspirate, Bone void filler, Fracture, Nonunion, Orthobiologics

Introduction

Fractures are a common cause of morbidity, lost productivity in the work force, and a significant driver of costs in the medical economy. Although exact numbers are difficult to identify, one Finnish registry study reported 53.4 fractures per 1000 person-years in women and 24.9 per 1000 person-years in men. Delayed healing and nonunion remain as significant complications in the treatment of fractures. Reported rates of delayed healing and nonunion approach 600,000 and 100,000 per year, respectively, in the United States alone.

Considerable research has been dedicated to improving the ultimate healing rate of fractures and preventing complications. Biologic augmentation and supplementation in the treatment of fractures is a pivotal area of development. The U.S. Food and Drug Administration definition of biologic treatment for fractures covers a wide range of therapies, including blood and blood components, stem cells, tissue grafts, recombinant proteins, and gene therapies. Biologic treatments in general are aimed at enhancing one or more aspects of the natural process of fracture healing. This includes stimulating cells with the capacity to form bone to actually do so (osteoinduction), augmenting the number or availability of cells capable of producing bone (osteogenesis), enhancing vascular growth and proliferation, and providing a scaffold conducive for cellular attachment and bone construction (osteoconductive). Although a comprehensive review of the available literature on biologic treatment of fractures is well beyond the scope of this textbook, this chapter seeks to provide an overview of currently available biologic treatments for fracture care.

When to Consider Biologic Augmentation

The majority of fractures (90%–95%) do not require biological enhancement and will heal uneventfully on their own with simple immobilization or standard internal fixation techniques. No definitive indications for biologic augmentation of fracture treatments exist. However, common indications cited in the literature include fracture nonunion and bony defects. Critical sized bone defects, commonly defined as greater than 50% circumferential bone loss or a 2 cm defect, may result from bone loss in open fractures or secondary to resection of infected bone at a fracture site. In either case, the healing potential of the fracture environment is not robust enough to result in bony union, whether the healing response is compromised or the size of the defect exceeds the body’s natural capability for fracture healing.

The selection of a particular biological adjuvant will depend on the specific clinical scenario. For instance, bone marrow aspirate (BMA) injection may be useful in the setting of stably fixed, aseptic nonunions of the tibia. Segmental defects may require more comprehensive treatment, such as autogenous bone graft, which contains vascular proliferative qualities and includes osteogenic, osteoinductive, and osteoconductive components. Patient factors such as the presence of infection, soft tissue coverage, or other medical problems may influence the decision as well. The remainder of this chapter will discuss the various biologic materials available to solve the clinical problems of nonunion and bone defects.

Autograft

Autograft is currently regarded as the gold standard for treatment of nonunions and bone defects and is the standard against which all other treatments are compared. It has multiple advantages. It is easy to obtain; is cheaper than most commercially available substitutes; is osteogenic, osteoinductive, and osteoconductive; and has a long track record of success in the literature. It can be obtained from a variety of anatomic sites, and there is no risk of disease transmission with its use. Disadvantages include donor site morbidity and limitations on available graft volume for large defects. The anterior and posterior iliac crests have historically been the most popular locations for graft harvesting. Chronic pain may be a complication at these sites, although there is evidence to show that the complication rate may be lower than previously reported. The reamer irrigator aspirator (RIA, Synthes, West Chester, PA) is an aspirating reamer that can be used to harvest bone from the intramedullary canal of the femur. There is evidence that bone harvested from the femur using the RIA has a higher concentration of growth factors than does iliac crest autograft. Higher volumes may be harvested using the RIA, as well. Studies have shown that the stem cells obtained from these reamings display similar osteogenic potential when compared with more conventionally harvested bone marrow stem cells. It has also been shown that the waste fluid from the RIA has elevated levels of osteoprotegerin, osteocalcin, and osteopontin, which are all known stimulators of bone formation. There is also level 1 evidence showing equivalent union rates and increased graft volume using the RIA compared with anterior iliac crest graft. Unique complications are possible, however, including iatrogenic femur fracture and exsanguination if appropriate technique is not used.

Bone Void Fillers

Synthetic bone void fillers, for the purposes of this chapter, are considered as biologic adjuvants because they provide an osteoconductive matrix to facilitate proliferation of bone. Some help to provide mechanical support, whereas others are meant to act as carriers for autogenous grafts, such as BMA. Bone void fillers, for example calcium phosphate and calcium sulfate, have no osteoinductive or osteogenic properties and may pose a challenge in the treatment of infections, as they can be difficult to completely remove without destroying normal bone.

Calcium phosphate is an injectable paste that hardens in the warm environment in the body, forming a mineral similar to, but with a higher compressive strength than, the mineral phase of bone. It is commonly used to augment fixation and stabilize metaphyseal defects, especially in the setting of periarticular fractures such as in the tibial plateau or distal radius. It is especially useful to support depressed articular fragments after reduction. There is level 1 evidence supporting the use of calcium phosphate over autogenous graft for preventing subsidence in depressed tibial plateau fractures ( Fig. 17.1 ).

Calcium phosphate is slowly resorbed by osteoclasts and replaced by lamellar bone over a period of usually a year or more. ( Fig. 17.2 )

Calcium sulfate is another option that typically comes in pellets or a powder that can be mixed with autogenous graft sources or powdered antibiotics and then molded into specific shapes. Calcium sulfate differs from calcium phosphate in that it has a lower compressive strength and is resorbed much more quickly. Because of this rapid resorption and weaker mechanical properties, it is more useful for increasing graft volume and for managing dead space while delivering antibiotics for the treatment of infection. An advantage over the use of poly-methyl methacrylate, which is nonresorbable, for making antibiotic beads is that a second surgery is not required for removal of the beads ( Fig. 17.3 ). However, wound drainage is a reported complication in the use of calcium sulfate.

Bone Morphogenic Protein in Fracture Healing

Bone morphogenic proteins (BMPs) are a group of signaling molecules that are part of the transforming growth factor beta (TGF-β) family and are known to be strong osteoinductive agents. For this reason there has been a great deal of interest to harness them for clinical use. There are currently two FDA-approved BMP products on the market: recombinant human BMP-2 (rhBMP-2) and recombinant human BMP-7 (rhBMP-7).

Two of the most notable randomized clinical trials investigating the use of rhBMP-2 are the BESTT trial and the BESTT-ALL trial. The BESTT trial reported on the effect of three treatment groups for open tibial shaft fracture: standard intramedullary nailing, intramedullary nailing plus rhBMP-2 in an absorbable collagen sponge at a concentration of 0.75 mg/mL, and intramedullary nailing plus rhBMP-2 in an absorbable collagen sponge at a concentration of 1.50 mg/mL. A total of 450 patients were randomized to these three groups, and a dose-dependent decrease in secondary intervention was observed. Additionally, a 21% increase in union rate at 6 months was found in the 1.50 mg/mL group when compared with control. Finally, there was a significant decrease in infection rate for Gustilo-Anderson type IIIA and IIIB fractures when the 1.50 mg/mL group was compared with control. It is difficult to determine at this time if a true relationship exists between BMP and infection prevention.

In the BEST-ALL trial, 30 patients with an average 4 cm residual cortical defect following intramedullary nailing for tibial shaft fractures were treated with either ICBG or a combination of allografts chips with an overlay of rhBMP-2 on an absorbable collagen sponge at a mean of 11 weeks after original nailing. The results were statistically equivalent between the two groups with union observed in 10/15 in the ICBG group and 13/15 in the rhBMP-2 group. No difference was found in functional outcomes.

Studies regarding rhBMP-7 have primarily focused on aseptic nonunion of the tibia. A randomized controlled trial comparing application of rhBMP-7 versus standard autograft (ICBG) found similar rates of union (81% and 84%) when used in conjunction with intramedullary nailing of tibial shaft nonunions. These results have been replicated in some case series, with a union rate of 89% seen for rhBMP-7 application with revision internal fixation of tibial shaft nonunion and a union rate of 87% seen for rhBMP-7 with revision fixation of long bone nonunion.

In summary, the literature supports the use of rhBMP-7 as a viable alternative to autogenous bone graft in long bone nonunion, although there should certainly be consideration for the increased price. The use of rhBMP-2 should likely be restricted to use in Gustilo-Anderson type III open fractures of the tibia.

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