Chapter 2

Fracture Repair and Bone Grafting

Christopher R. Brown, MD *Scott D. Boden, MD

Introduction An understanding of bone healing and graft incorporation is fundamental to the practice of orthopaedics. Regardless of their particular specialty within orthopaedics, surgeons must have a firm grasp of the biology of bone healing and grafting. It is a necessary part of the armamentarium when treating acute fractures, nonunions, bone defects, angular deformity, limb-length inequality, and arthrodeses of the spine and extremities. The number of spinal fusion surgeries has steadily increased over the past decade. Currently there are more than 250,000 spine fusion surgeries performed in the United States each year. Since the 1990s, spinal arthrodesis has become the most common reason for autologous bone grafting. To ensure a good outcome for these patients, the surgeon must have knowledge of a broad range of treatment methods and strategies. Bone healing and graft incorporation is a complex process that involves molecular, cellular, local, and mechanical factors. All of these processes must be effectively managed for bone healing to be successful. The surgeon must identify deficiencies in the process and intervene in an appropriate manner. Advances have been made recently in the field of bone tissue engineering, giving the surgeon practical clinical benefits in treating patients.

that causes the fracture. The fracture causes a disruption of both the periosteal and endosteal blood supply, leading to local necrosis. The surrounding soft tissue is usually damaged, leading to even more extensive disruption of the blood supply. Local cells release vasoactive mediators that cause increased vasodilatation and permeability. This leads to a steady increase in blood flow that peaks approximately 2 weeks after fracture. A hematoma forms that is invaded by inflammatory cells. Fibroblasts appear and produce collagen and eventually replace the hematoma with granulation tissue. For long bone fractures, the repair phase begins with the formation of a soft callus usually between day 5 and day 21 (Figure 1). There is a dramatic invasion of new blood vessels formed by endothelial progenitor cells, resulting in a revascularization phase. Progenitor cells invade the environment and differentiate according to the local conditions at the site. The differentiation is mostly influenced by the oxygen tension, mechanical environment, and signals from local growth factors. High strain environments promote differentiation of cells that produce fibrous tissue. Osteoprogenitor cells proliferate in areas of increased oxygen tension and decreased strain. Areas of high oxygen tension and

1: Principles of Orthopaedics

Bone Fracture Healing The overall fracture incidence is 11.3 in 1,000 patients per year11.67 in 1,000 per year in males, and 10.65 in 1,000 per year in females.1 Acute fractures of bone result from forces to the skeleton that exceed the strength of the tissue. The severity of the injury is directly related to the intensity and duration of the force. A bone fracture initiates a cascade of events that can restore the injured bone to its original state. The first stage, inflammation, begins at the time of the impact

*Scott D. Boden, MD or the department with which he is affiliated has received research or institutional support from Medtronic, DePuy, Synthes, and Abbott, miscellaneous nonincome support, commercially derived honoraria, or other nonresearch related funding from Osteotech, royalties from Medtronic and Osteotech, and is a consultant or employee for Medtronic.
American Academy of Orthopaedic Surgeons

Figure 1

Early repair. There is organization of the hematoma, early primary new bone formation in subperiosteal regions, and cartilage formation in other areas.

Orthopaedic Knowledge Update 9

13

Section 1: Principles of Orthopaedics

Table 1

Local and Systemic Factors Influencing Bone Healing

Positive Factors
Good vascular supply at the graft site Large surface area Mechanical stability Mechanical loading Growth factors

Negative Factors
Radiation Tumor Mechanical instability Infection Corticosteroids Chemotherapy Smoking Diabetes Malnutrition Metabolic bone disease

low strain tend to promote formation of woven bone directly; this is referred to as intramembranous bone formation. Regions of intermediate strain and low oxygen tension will have chondrocyte differentiation and cartilage formation. A fibrocartilaginous callus then bridges the fracture site. The cartilage can reduce the local strain and lead to bone formation. The chondrocytes and cartilage matrix calcify, and progenitor cells develop into osteoblast and deposit new bone, replacing the calcified cartilage in a process known as endochondral bone formation. The final stage in fracture repair, remodeling, involves conversion of immature woven bone into lamellar bone. It occurs in response to the local loading environment. Osteoclast resorption of woven bone is coupled with osteoblast deposition of mature lamellar bone. It ends when the bone has resumed its normal appearance, and the medullary canal is reconstituted. The mechanical properties of the bone return to that of the preinjured bone. Some but not all of the basic biologic process and mechanisms involved in fracture healing apply to bone graft sites. Much has been learned about the biology of bone grafting by studying spine fusion models. This environment is very different from that of a healing long bone fracture. The biology and maturation of a spine fusion differs among the various types of fusion locations. The interbody spine environment is rich in decorticated bone surface area, which can increase the access to bone marrow that contains osteoprogenitor cells required to form new bone. It is also subject to compressive forces that seem to stimulate remodeling and loading of bone. This biologic environment can result in generally higher fusion rates if there is adequate access to bone marrow, rigid internal fixation to avoid shearing of new blood vessels, and adequate end plate strength to prevent subsidence of the structural component of the interbody graft or spacer.2 14

1: Principles of Orthopaedics

An intertransverse process spine fusion is a very different environment. There is less access to bone marrow and more abundant muscle tissue, and it is subject to tensile loads. Compressive loads are less significant until the graft has consolidated. The intertransverse fusion healing process in rabbits using iliac crest bone graft has been described.3 Analysis of histologic sections revealed three distinct and temporal phases of spine fusion healing: inflammatory, reparative, and remodeling. These phases occur throughout the fusion mass but at different times. Maturation of the fusion mass was most advanced in the regions near the decorticated transverse processes, which represent the major blood and progenitor cell supply to the fusion mass. In these transverse process zones, intramembranous formation was the major means of bone formation. In the central zone, a similar process occurred but it was delayed in time and included a period of endochondral bone formation in which cartilage was replaced by bone. This lag effect may explain why nonunions most often occur at this central zone.3 Molecular biology studies have shown a predictable sequence of gene expression during the maturation of the fusion mass. Various proteins including collagen, osteocalcin, and bone morphogenetic proteins (BMPs) have a temporal and spatial pattern of expression. Consistent with the histologic analysis, peak expression of the genes was seen 1 to 2 weeks earlier in the areas closest to the decorticated transverse processes than in the central zones, which are farther from the decorticated host bone.4

Factors Affecting Bone Healing Many factors affecting bone healing and grafting must be considered when formulating a treatment plan for a patient with a fracture or nonunion or when considering an elective arthrodesis procedure (Table 1). Some of these factors are beyond the control of the surgeon, whereas others can be manipulated to achieve a successful outcome. Patient factors directly affect bone formation. The nutritional status of the patient must be considered and maximized before elective procedures. Medications the patient may be taking can adversely affect the biologic process needed for healing. Nonsteroidal antiinflammatory drugs have been linked to delayed bone healing. However, it is unclear whether cyclooxygenase2-selective nonsteroidal anti-inflammatory drugs will have less effect on healing than nonselective drugs.5,6 Patients taking fluoroquinolones may experience decreased healing during the early stages of fracture healing.7,8 Nicotine, steroids, and some chemotherapeutic agents have proved to have a deleterious effect on bone healing and graft incorporation. In the rabbit spine fusion model, the administration of nicotine inhibits the gene expression of a wide range of cytokines, including those associated with neovascularization and osteoblast differentiation.9 Using the same model, a single dose of doxorubicin at the time of surgery appears to play a

Orthopaedic Knowledge Update 9

American Academy of Orthopaedic Surgeons

Chapter 2: Fracture Repair and Bone Grafting

significant inhibitory role in the process of spinal fusion.10 Patient comorbidities impact the biologic response to a fracture. Diabetes is known to cause impaired bone healing. In a 2005 study, diabetic patients with ankle fractures were retrospectively reviewed.11 Patients with one or more comorbidities from diabetes were at an increased risk of developing complications from an ankle fracture that included nonunion, malunion, and the need for prolonged bracing.11 The presence of human immunodeficiency virus (HIV) may increase the risk of nonunion and infection.12 The soft tissue surrounding the fracture can have an impact on the biology of bone healing. Surgeons are aware of the importance of limiting iatrogenic softtissue trauma during surgical intervention. The advent of intramedullary nails and sliding plates with percutaneous fixation allows a surgeon to avoid the injury zone, minimizing further compromise to the soft tissue and blood supply. The value of early soft-tissue coverage for open tibia fractures demonstrates the importance of the soft-tissue envelope. Mechanical factors play a role in fracture healing and bone graft maturation. The rigidity of the fixation can affect the type of healing that occurs. Callus-free primary bone healing requires direct bone apposition and absolute stability. Rigid internal fixation using either a lag screw or a compression plate provides the mechanical stability needed for direct bone healing. Unlocked intramedullary nails and external fixators are examples of load-sharing devices that create a different biologic environment. The micromotion in the fracture leads to indirect bone healing, evidenced by the presence of a cartilaginous callus. There has been a recent shift toward the use of less rigid fixation to allow load sharing, which results in callus formation.

autogenous graft or the coverage of a larger grafting volume with similar healing success rates. A graft enhancer, when added to autogenous graft, should result in higher fusion success rates. A graft substitute can be used in place of autogenous bone graft with the requirement that it results in similar or better fusion success rates. The specific biologic roles required of a graft will depend on the specific healing environment. For example, a tibial metaphyseal fracture is one of the least challenging healing environments after external fixation because of the high prevalence of bone marrow access, vascular supply, and protection from soft-tissue interposition. Purely osteoconductive materials usually perform well in these situations, but an osteoinductive component may be helpful in healing-impaired hosts (smokers, diabetics, steroid users). At the other extreme, posterolateral lumbar spine fusion is one of the most biologically challenging healing environments. In this case, purely conductive materials are not effective substitutes and are only variably effective as extenders. In this situation a graft enhancer or substitute with some osteoinductive properties is likely required. One exception is pediatric patients, in whom purely conductive materials function better than in adults undergoing spine fusion.

Current Graft Options

Autogenous Bone Grafts Autogenous iliac crest bone graft is the most welldocumented bone graft and has been the gold standard for grafting material in patients undergoing spinal fusion. It has osteogenic properties (numerous differentiated and undetermined stromal cells within the marrow cavity lining) and osteoconductive properties (ideal scaffold). Cancellous bone contains only minute amounts of BMPs, which are not active; therefore, according to strict definitions autologous bone graft material is not osteoinductive. A commonly used site for harvesting bone graft is the posterior iliac crest, because it provides a large quantity of both cancellous and corticocancellous bone. With cancellous bone grafts, approximately 15% of the osteoblasts and osteocytes of the graft survive and are capable of producing early bone.14 The porous nature of cancellous bone permits more rapid ingrowth of new blood vessels, which allow for the influx of osteoblast precursors. Bone formation and resorption usually occur concomitantly, with osteoclasts resorbing the dead trabecular bone followed by osteoblasts depositing new bone (creeping substitution). Eventually, all grafted cancellous tissue is remodeled with new host bone and marrow. One disadvantage of autograft is the limited amount of graft material available for use. The quantity and quality of iliac donor bone can be diminished substantially in older patients with osteoporosis or fatty marrow infiltration. Significant donor-site morbidity has been reported in as many as 25% to 40% of patients. Complications include chronic donor-site pain, infection, fracture, and hematoma.15 15
1: Principles of Orthopaedics

Classification of Graft Material A bone grafting material may possess several properties. An osteoconductive material needs to provide the scaffolding to support new bone formation. The proper three-dimensional structure of the graft permits the ingrowth of sprouting capillaries, perivascular tissue, and osteoprogenitor cells, facilitating the process of graft incorporation known as creeping substitution. An osteoinductive substance will stimulate the recruitment and differentiation of mesenchymal stem cells (MSCs) into bone-forming cells. Specific BMPs are the primary known osteoinductive proteins BMP-2, -4, -6, -7, and -9. An osteogenic graft contains viable osteoblastic cells that are capable of direct bone formation. This potential to provide bone-forming cells is characteristic of only fresh autogenous bone graft. Other grafts rely on recruitment of host progenitor cells to differentiate into boneforming cells.13 Bone graft materials can be classified into three functional biologic roles. All three roles are measured with reference to autogenous bone graft, the historic gold standard. A bone graft extender allows the use of less

American Academy of Orthopaedic Surgeons

Orthopaedic Knowledge Update 9

Section 1: Principles of Orthopaedics

Biologic Enhancers of Bone Healing

Platelets/Autologous Growth Factor

Platelet concentrate preparation systems have gained some measure of use in spinal fusion augmentation. Platelets are rich in growth factors such as plateletderived growth factor and transforming growth factor-, and it has been argued that platelet concentrates therefore are helpful in bone formation. Much of the data are derived from oral and maxillofacial surgery, where membranous bone formation is much easier than spinal bone formation. Many spine surgeons believe that growth factors are good and that platelet concentrates may help and cannot hurt. Unfortunately, the evidence for efficacy in spinal surgery has not been established as clearly as the other biologics discussed above. In fact, some clinical data suggest either no efficacy or a detrimental effect. A retrospective cohort study of patients treated by a single surgeon who performed consecutive single-level posterolateral lumbar fusion showed that those with iliac crest bone alone (n = 27) had a 91% rate of fusion and those with iliac crest augmented with autologous growth factor (AGF) (n = 32) had a 62% rate of fusion.16 In a retrospective cohort study of posterolateral lumbar fusions with autograft iliac crest mixed with a platelet concentrate (AGF) (n = 76 consecutive patients), the nonunion rate was 25%, compared with a case control cohort (n = 76 patients) in which the nonunion rate was 17%.17 The authors noted the increase in cost and risk to the patient with use of AGF and recommended against using AGF for instrumented posterolateral lumbar fusion.

some beneficial effects on wound and tendon healing. A broad spectrum of experiments performed at the basic science and clinical levels have provided substantial evidence that low-intensity ultrasound can accelerate osteogenesis and augment the fracture healing process.

Allograft Allograft bone products are the most common substitutes for autogenous bone grafts. Some advantages of allograft include its availability in greater quantities and precut sizes/shapes than autograft and avoidance of the donor-site morbidity associated with autograft. The sterilization process kills the cells in the allograft and may damage other components including proteins. Therefore, these materials are highly osteoconductive but not osteogenic because the cells do not survive transplantation. As with mineralized autograft, mineralized allograft is not inherently osteoinductive. In treating nonunions, bone void defects, and posterolateral spine fusions, allograft typically is used as a bone graft extender. Cancellous chips are added to local or iliac bone to increase the volume of the graft. Allograft cancellous chips function poorly when used alone for posterior lumbar fusions in adults.19 The most suitable patient for nonstructural (morcellized) allografts in spine surgery appears to be the adolescent undergoing posterior fusion for scoliosis. Allograft chips are successful in these patients because bone heals easily in adolescents and the posterior thoracic spine is very stable with fixation and has a larger surface area for decortication.20 Impaction bone grafting uses morcellized femoral head allograft to restore femoral and acetabular bone stock in the setting of revision joint arthroplasty. It has been shown to provide initial stability and restore long-term bone stock in the distal femur. This technique is associated with an excellent long-term prosthetic survival rate in both acetabular and femoral reconstruction.21,22 Allograft can also be used for its structural, weightbearing properties. These grafts can be used in reconstructive surgery when large bony defects necessitate structural supports, such as a femoral or acetabular deficiency. Structural allograft also can be used for interbody spine fusion alone or in combination with a graft enhancer or osteoinductive material.23 More than 200,000 bone allografts are used in musculoskeletal procedures annually in the United States.24 Tissue banks have been established to ensure a supply of high-quality allogenic tissue for reconstructive orthopaedic surgery. More than 50 tissue banks in the United States are accredited by the American Association of Tissue Banks (AATB). The US Food and Drug Administration (FDA) and the AATB help ensure adequate screening of tissue donors and that the allograft provided by the various tissue banks is properly processed, labeled, and distributed. A recent event raised questions about the safety of allograft. In September 2005, the FDA received a report that a tissue recovery firm had inaccuracies in

1: Principles of Orthopaedics

Growth and Differentiation Factor-5

Growth and differentiation factor-5 (GDF-5) is known by many different names including MP-52, LAP-4, CDMP-1, BMP-14, and radotermin. GDF-5 has been shown to promote tissue regeneration in bone, cartilage, soft tissue, and tendon in vivo. The rabbit intertransverse process fusion experiments with GDF-5 indicate that 100% fusion rates can be achieved; however, the lowest concentration used (0.5 mg/mL) resulted in the highest bone volume formation when compared with higher doses (1.0 mg/mL and 1.5 mg/mL).18 This and other studies indicate that increasing the dose too much with this molecule may be counterproductive to bone formation. Currently, two multicenter investigational device exemption clinical trials are ongoing, one for spinal fusion and another for long bone repair.

Ultrasound
Ultrasound is acoustic radiation at frequencies beyond the limit of human hearing. It has been used as a physical signal in the detection or alteration of biologic effects for many years. Very low ultrasonic intensities (milliwatts per cm2) are applied for diagnostic purposes to avoid excessive heating of the tissues, and ultrasonic intensities of 1 to 3 W/cm2 are commonly used in the treatment of joint stiffness, pain, and muscle spasm and to improve muscular mobility. Ultrasound also has 16

Orthopaedic Knowledge Update 9

American Academy of Orthopaedic Surgeons

Chapter 2: Fracture Repair and Bone Grafting

their donor records. The FDA investigation determined that human donors were not properly screened for certain infectious diseases and that some of the donors may not have met eligibility requirements. In October 2005, tissues from this tissue recovery firm were recalled and the company was ordered to cease manufacturing and to retain all cellular and tissue-based products.25 Screening of cadaveric donors begins with a detailed questionnaire completed by the life partner or next of kin. Donors are excluded if there is a history of the following factors or conditions: exposure to specific communicable diseases, unprotected sexual contact, drug use, neurologic diseases, autoimmune diseases, collagen disorders, or metabolic diseases. Viral disease transmission, including hepatitis C, hepatitis B, and HIV, is of utmost concern. Since 1980, two cases of HIV transmission as a result of musculoskeletal allograft have been reported.26 However, since the AATB adopted strict screening programs and mandatory blood tests for all donors, the incidence of disease transmission has been halted. Allograft bone can be processed many different ways, including low-dose (< 20 kGy) irradiation, physical dbridement, ultrasonic or pulsatile water washes, ethanol treatment, and antibiotic soaking (4 C for at least 1 hour).27 The goal of processing is to ensure sterility while retaining certain biologic and biomechanical properties. Terminal sterilization by gamma irradiation, electron beam irradiation, or ethylene oxide treatment may be used if there is contamination, but there is a dose-dependent effect on the mechanical strength of the graft.28

new bone at the interface, but no clear clinical advantage has been shown.32

Collagen
The structure of collagen is conductive to mineral deposition, vascular ingrowth, and growth factor binding; however, it provides little or no structural support. Its use as a stand-alone bone graft substitute has been unsuccessful. It does potentiate the effects of other osteoconductive and osteoinductive substances, including bone marrow and composites of hydroxyapatite and tricalcium phosphate. Its future role will most likely be as an ingredient in bone graft substitute composites.

Coralline Substitutes
The exoskeleton of certain naturally occurring marine corals has many similarities with bone. A number of animal studies have shown the biocompatibility and bioactivity of coralline implants.33 Vascular tissue readily migrates into its matrix. Either of two general processes is used to prepare marine corals for implantation. The first is a process that uses the calcium carbonate exoskeleton directly after it has undergone a detergent-based process to remove the organic phase of the coral organism. The second general process converts calcium carbonate to hydroxyapatite by a hydrothermal reaction. Both processes result in a coralline product with an osteoconductive matrix that can be used as a bone graft extender.
1: Principles of Orthopaedics

Osteoconductive Bone Graft Substitutes

Ceramics
Ceramics containing calcium phosphate are formed by heating and pressurizing these nonmetallic materials. The calcium phosphates are the most commonly used ceramics in orthopaedics.29 As osteoconductive materials, they are mostly used as bone graft extenders. Ceramics have the advantage of inducing little inflammatory response and pose little or no risk of disease transmission. They are also available in unlimited quantities and have no donor-site complication. The disadvantages include low fracture resistance and tensile strength. Several animal studies using ceramics as adjuncts to posterolateral fusions have yielded conflicting results. There are clinical data showing comparable results for posterolateral lumbar fusions in patients with idiopathic scoliosis using ceramics and local bone versus local bone and autograft.30 The best clinical experience with the ceramics has been in the setting of anterior interbody fusion in the cervical spine.31 Hydroxyapatite, another ceramic, has been available as a coating on joint arthroplasty implants for some time. Animal studies showed that such coatings increase fixation strength by preferential deposition of

Beta-tricalcium phosphate (-TCP) bone void filler has been developed to mimic the trabecular structure of natural cancellous bone (Vitoss, Orthovita, Malvern, PA). The pores in -TCP encourage vascularization and bone ingrowth. There has been a shift in bone void fillers from very slowly degradable ceramics (hydroxyapatite) to more rapidly resorbed materials (such as the tricalcium phosphates). A few retrospective studies have evaluated the efficacy of -TCP in spinal surgery, and controlled clinical studies are being conducted. However, it will most likely play a role in the future as a bone graft extender in arthrodesis surgery.34

Beta-Tricalcium Phosphate

Osteoinductive Bone Graft Substitutes

Demineralized Bone Matrix

Demineralized bone matrix (DBM) is produced by the decalcification of cortical bone. In 1965, the osteoinductive capability of DBM was first reported.13,35 The ideal demineralization process removes the calcium and phosphate but leaves the extracellular matrix, which consists predominantly of type I collagen and nonstructural proteins. Included in these proteins are growth factors, the most important of which is BMP. DBM provides no structural strength but it may function as an osteoinductive and conductive material if properly processed and assembled into a final formulation. The degree of osteoinductivity is highly variable between 17

American Academy of Orthopaedic Surgeons

Orthopaedic Knowledge Update 9

Section 1: Principles of Orthopaedics

different manufacturers of DBM and the various final formulations.36 DBM has variable efficacy based on details of the preparation, carrier material, terminal sterilization, and the environment being tested.37 Because DBM was regulated as a minimally manipulated tissue (until 2005), extensive studies were not required by the FDA. Therefore, most types of DBM do not have prospective clinical trials demonstrating their efficacy. A prospective randomized clinical study has shown that Grafton DBM (Osteotech, Eatontown, NJ) can be used to extend autograft iliac crest in a 2:1 ratio (Grafton to autograft) and achieve equivalent bone formation in posterolateral instrumented fusion (n = 81).38

Bone Morphogenetic Proteins

The BMPs comprise a family of at least 15 structurally related, low-molecular-weight noncollagenous glycoproteins that belong to the transforming growth factor- superfamily.39 The BMPs play an important role in embryonic organ development including endochondral and intramembranous bone formation and are believed to promote the normal healing process after fractures. BMPs are known to bind to specific receptors on a variety of different cell types, including MSCs, osteoblasts, and osteoclasts. With lower concentrations, BMPs promote the differentiation of MSCs into chondrocytes, which lay down a cartilaginous matrix. This matrix then calcifies, is invaded by blood vessels, and remodels into mature bone, a process termed endochondral bone formation. At higher concentrations, BMPs can induce direct bone formation, recapitulating normal intramembranous bone formation.40 The proportion of intramembranous versus endochondral bone formation depends on numerous factors, including the concentration of BMP, the carrier, and the site of implantation. BMP-2 A large body of work supports the efficacy of BMP-2 as a bone graft substitute. The efficacy of BMP-2 in the treatment of tibia fractures with cortical defects has demonstrated its ability to function as a substitute for iliac crest bone grafting.41 Most of the work on the BMPs has been done in evaluating their efficacy as a bone graft substitute for use in patients with spinal arthrodesis. Sufficient preclinical studies were performed to determine the appropriate dose and carrier for preclinical models and resulted in 100% spinal fusion rates in most studies. This preparatory work was followed by level 1 prospective clinical trials that then resulted in FDA approval for recombinant human BMP-2 (rhBMP-2) (INFUSE, Medtronic Sofamor Danek, Minneapolis, MN) within a titanium lumbar interbody cage (LT-CAGE, Medtronic Sofamor Danek) for anterior lumbar interbody fusion. As measured by CT scans, anterior lumbar interbody fusion rates were 99.8% for rhBMP-2 (n = 143) and 95.6% for iliac crest (n = 136) at 2-year follow-up.42 On the strength of these excellent results, INFUSE was approved by the FDA in 2002. 18

However, this dose and carrier of rhBMP-2 was not consistently effective in the posterolateral application, and changes were made. Using a ceramic carrier (instead of a collagen sponge) and a concentration of 2.0 mg/mL and total dose of 20 mg per side in a human posterolateral fusion pilot experiment, a fusion rate of 100% (20 of 20) for BMP-2 and 40% (2 of 5) for iliac crest was achieved.43 In a more recent study of 74 patients with a minimum 1-year follow-up, the rhBMP-2 group had statistically higher fusion grades at both 6 months and 12 months of follow-up in comparison with the iliac crest group.44 The concentration of rhBMP-2 used was 2.0 mg/mL in 10 mL of a ceramic matrix called compression-resistant matrix; this preparation of rhBMP-2 was placed on both sides of the spine, resulting in a total dose of 40 mg of rhBMP-2. FDA approval for posterolateral fusion application of rhBMP-2 is likely in the near future. BMP-2 has been investigated in a prospective, randomized clinical trial of open tibia fractures. The group that received BMP-2 at the time of definitive closure had fewer bone grafting procedures, fewer patients requiring secondary invasive surgeries, and a lower rate of infection compared with the control group. These clinical trials established the clinical efficacy of BMP-2 combined with an absorbable collagen sponge in the treatment of open tibial fractures.45 BMP-7 BMP-7 (osteogenic protein-1 [OP-1]) is another osteoinductive molecule that has undergone extensive study. Preclinical studies have met with success, and clinical studies have been ongoing for some time. The first clinical study for OP-1 involved treatment of nonunion of open tibia fractures.46 The authors found that 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had radiographic union.46 An uninstrumented posterolateral fusion pilot study was conducted with 3.5 mg of OP-1 in 1 g of carboxymethylcellulose resulting in 0.875 mg/mL of OP-1 concentration.47,48 The 1-year follow-up of this study resulted in fusion rates of 74% (14 of 19) in the OP-1 patients and 60% (6 of 10) in the iliac crest bone group, but a subsequent 2-year follow-up resulted in fusion rates of 55% (11 of 20) for OP-1 and 40% (4 of 10) for iliac crest patients. The pivotal FDA study for OP-1 used in posterolateral fusion has not yet been published. However, OP-1 is now available on the basis of an FDA humanitarian device exemption for long bone fractures and spine posterolateral nonunions.

1: Principles of Orthopaedics

Future Directions The future will likely provide alternative strategies for delivery of osteoinductive proteins such as BMPs. The delivery of the gene for a BMP so that the protein can be synthesized on site is one alternative that is being investigated. In a rodent study, the gene for BMP was

Orthopaedic Knowledge Update 9

American Academy of Orthopaedic Surgeons

Chapter 2: Fracture Repair and Bone Grafting

successfully delivered by an injection of a modified adenovirus resulting in a percutaneous posterolateral spine fusion.49 However, the challenges related to safety of gene therapy will need to be overcome. As an alternative to delivering the gene for a single BMP, some investigators have identified a gene that seems to coordinate expression of multiple BMPs. This intracellular signaling protein is named LIM mineralization protein-1. This gene has been tranfected into bone marrow cells of rats and reimplanted into posterolateral fusion beds. It proved effective for promoting a solid fusion.50 The future will also bring a need for strategies to approach regional and systemic bone formation as a means of preventing fractures before they occur and treating a variety of metabolic bone disorders. A continued improved understanding of the biology of bone healing should help this effort.

trovafloxacin inhibition of experimental fracturehealing. Clin Orthop Relat Res 2003;414:95-100. 8. Huddleston PM, Steckelberg JM, Hanssen AD, Rouse MS, Bolander ME, Patel R: Ciprofloxacin inhibition of experimental fracture healing. J Bone Joint Surg Am 2000;82:161-173. Theiss SM, Boden SD, Hair G, Titus L, Morone MA, Ugbo J: The effect of nicotine on gene expression during spine fusion. Spine 2000;25:2588-2594. Tortolani PJ, Park AE, Louis-Ugbo J, et al: The effects of doxorubicin (adriamycin) on spinal fusion: An experimental model of posterolateral lumbar spinal arthrodesis. Spine J 2004;4:669-674. Results indicate that there were no significant differences in wound complications with doxorubicin administration in the animal model studied. A single dose of doxorubicin administered intravenously at the time of surgery appears to play a significant inhibitory role in the process of spinal fusion. If similar effects occur in humans, these data suggest that doxorubicin would be detrimental to bone healing in a spine fusion if administered during the perioperative period. Jones KB, Maiers-Yelden KA, Marsh JL, Zimmerman MB, Estin M, Saltzman CL: Ankle fractures in patients with diabetes mellitus. J Bone Joint Surg Br 2005;87: 489-495. In this retrospective review, 42 patients with diabetes mellitus and a closed rotational ankle fracture were compared with matched controls without diabetes mellitus. Patients without comorbidities from diabetes mellitus had complication rates equal to controls. Those diabetics with comorbidities had a higher complication rate in regard to infection; below-knee amputation; and nonunion, malunion, or Charcot neuroarthropathy (47% versus 14%). Harrison WJ, Lewis CP, Lavy CB: Open fractures of the tibia in HIV positive patients: A prospective controlled single-blind study. Injury 2004;35:852-856. The authors prospectively studied 27 patients with severe open fractures and analyzed infection and union as outcome measures. Seven patients were HIV positive, and 20 patients HIV negative. Wound infection and delayed union were more common in HIV positive patients. Urist MR: Bone: Formation by autoinduction. Science 1965;150:893-899. Ebraheim NA, Elgafy H, Xu R: Bone-graft harvesting from iliac and fibular donor sites: Techniques and complications. J Am Acad Orthop Surg 2001;9: 210-218. Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA: Complications of iliac crest bone graft harvesting. Clin Orthop Relat Res 1996;329:300-309. Weiner BK, Walker M: Efficacy of autologous growth

9.

10.

Annotated References
1. Court-Brown C, Koval K: The epidemiology of fractures, in Bucholz RW, Heckman JD, Court-Brown C, et al (eds): Rockwood and Greens Fractures in Adults, ed 6. Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp 96-143. A general discussion of fracture epidemiology is presented. Boden SD, Schimandle JH: Biologic enhancement of spinal fusion. Spine 1995;20:113S-123S. Boden SD, Schimandle JH, Hutton WC, Chen MI: The use of an osteoinductive growth factor for lumbar spinal fusion: Part I. The biology of spinal fusion. Spine 1995;20:2626-2632.8747240 Morone MA, Boden SD, Martin G, et al: Gene expression during autograft lumbar spine fusion and the effect of bone morphogenetic protein-2. Clin Orthop Relat Res 1998;351:252-265. Brown KM, Saunders MM, Kirsch T, Donahue HJ, Reid JS: Effect of COX-2-specific inhibition on fracturehealing in the rat femur. J Bone Joint Surg Am 2004; 86-A:116-123. A nondisplaced unilateral fracture was created in the right femur of 57 adult male rats. Rats were given either no drug, indomethacin (1 mg/kg/d), or celecoxib (3 mg/kg/d) daily, starting on postoperative day 1. At 4 weeks, only the indomethacin group showed biomechanical and radiographic evidence of delayed healing. Gerstenfeld LC, Thiede M, Seibert K, et al: Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal antiinflammatory drugs. J Orthop Res 2003;21:670-675. Perry AC, Prpa B, Rouse MS, et al: Levofloxacin and 12.

11.

1: Principles of Orthopaedics

2.

3.

4.

5.

13.

14.

6.

15.

7.

16.

American Academy of Orthopaedic Surgeons

Orthopaedic Knowledge Update 9

19

Section 1: Principles of Orthopaedics

factors in lumbar intertransverse fusions. Spine 2003; 28:1968-1970. 17. Carreon LY, Glassman SD, Anekstein Y, et al: Platelet gel (AGF) fails to increase fusion rates in instrumented posterolateral fusions. Spine 2005;30:E243-E246. Results from this study showed that platelet gel failed to enhance the fusion rate when added to autograft in patients undergoing instrumented posterolateral spinal fusion, and is therefore not recommended to supplement autologous bone graft during instrumented posterolateral spinal fusion. Magit DP, Maak T, Trioano N, et al: Healos/rhGDF-5 induces posterolateral lumbar fusion in a New Zealand white rabbit model. Spine 2006;31:2180-2188. Healos/rhGDF-5 induced fusion in 100% of the rabbits studied, compared with a 38% fusion rate induced by autograft. Overall, these results support continued research of Healos/rhGDF-5 as a potential bone graft alternative. Jorgenson SS, Lowe TG, France J, Sabin J: A prospective analysis of autograft versus allograft in posterolateral lumbar fusion in the same patient: A minimum of 1-year follow-up in 144 patients. Spine 1994;19:20482053. Dodd CA, Ferguson CM, Freedman L: Allograft versus autograft bone in scoliosis surgery. J Bone Joint Surg Br 1988;70:431-434. Schreurs BW, Arts JJ, Verdonschot N, Buma P, Slooff TJ, Gardeniers JW: Femoral component revision with use of impaction bone-grafting and a cemented polished stem: Surgical technique. J Bone Joint Surg Am 2006; 88:259-274. Thirty-three consecutive femoral reconstructions that were performed between March 1991 and February 1996 with use of the X-change femoral revision system, freshfrozen morcellized allograft, and a cemented polished Exeter stem were followed prospectively. No femoral reconstruction had been rerevised at a mean of 10.4 years postoperatively. Femoral revision with use of an impaction bone grafting technique and a cemented polished stem resulted in an excellent prosthetic survival rate at 8 to 13 years postoperatively. The major complication that occurred was a femoral fracture in four patients. Schreurs BW, Busch VJ, Welten ML, Verdonschot N, Slooff TJ, Gardeniers JW: Acetabular reconstruction with impaction bone-grafting and a cemented cup in patients younger than fifty years old. J Bone Joint Surg Am 2004;86-A:2385-2392. Impaction bone grafting technique was used for 23 primary and 19 revision acetabular reconstructions. Twenty-eight patients (31 hips) were available for review after a minimum duration of follow-up of 15 years. All 28 hips (in 25 patients) had retention of the acetabular component for a minimum of 15 years. Zdeblick TA, Ducker TB: The use of freeze-dried allograft bone for anterior cervical fusions. Spine 1991; 16:726-729.

24.

Tomford WW, Mankin HJ: Bone banking: Update on methods and materials. Orthop Clin North Am 1999; 30:565-570. Centers for Disease Control and Prevention: Brief report: Investigation into recalled human tissue for transplantationUnited States, 2005-2006. MMWR Morb Mortal Wkly Rep 2006;55:564-566. This article discusses details of the FDA investigation into a human tissue processing companys violations of the Current Good Tissue Practice Rules of 2005. Transmission of HIV through bone transplantation: Case report and public health recommendations. MMWR Morb Mortal Wkly Rep 1988;37:597-599. Chase SW, Herndon CH: The fate of autogenous and homogenous bone grafts. J Bone Joint Surg Am 1955; 37:809-814. Jinno T, Miric A, Feighan J, Kirk SK, Davy DT, Stevenson S: The effects of processing and low dose irradiation on cortical bone grafts. Clin Orthop Relat Res 2000; 375:275-285. Muschler GF, Negami S, Hyodo A, Gaisser D, Easley K, Kambic H: Evaluation of collagen ceramic composite graft materials in a spinal fusion model. Clin Orthop Relat Res 1996;328:250-260. Delecrin J, Takahashi S, Gouin F, Passuti N: A synthetic porous ceramic as a bone graft substitute in the surgical management of scoliosis: A prospective, randomized study. Spine 2000;25:563-569. McConnell JR, Freeman BJ, Debnath UK, et al: A prospective randomized comparison of coralline hydroxyapatite with autograft in cervical interbody fusion. Spine 2003;28:317-323. McPherson EJ, Dorr LK, Gruen TD, Saberi MT: Hydroxyapatite coated proximal ingrowth femoral stems: A matched pair control study. Clin Orthop Relat Res 1995;315:223-230. Khan SN, Fraser JF, Sandhu HS, Cammisa F, Girardi FP, Lane JM: Use of osteopromotive growth factor demineralized bone matrix and ceramics to enhance spine fusions. J Am Acad Orthop Surg 2005;13: 129-137. Autogenous growth factor concentrate, bovine bonederived osteoinductive protein, and recombinant human MP52 may be used to enhance fusion rates; however, there are few studies that have assessed their efficacy. Epstein NE: A preliminary study of the efficacy of beta tricalcium phosphate as a bone expander for instrumented posterolateral lumbar fusions. J Spinal Disord Tech 2006;19:424-429. The efficacy of Vitoss -TCP, an artificial bone substitute, combined with lamina autograft (50:50 mix) in 40 prospective posterolateral fusions using pedicle/screw instrumentation was analyzed. By the sixth postopera-

25.

26. 18.

27.

28. 19.

29.

20.

1: Principles of Orthopaedics

30.

21.

31.

32.

33.

22.

34.

23.

20

Orthopaedic Knowledge Update 9

American Academy of Orthopaedic Surgeons

Chapter 2: Fracture Repair and Bone Grafting

tive month, fusion was neuroradiologically confirmed on both dynamic radiographs and CT studies for 26 of 27 single level fusions (1 pseudarthrosis) and 11 of 13 two-level fusions (L4-S1). 35. Urist MR, Silverman BF, Buring K, Dubuc FL, Rosenberg JM: The bone induction principle. Clin Orthop Relat Res 1967;53:243-283. Bae HW, Zhao L, Kanim LE, Wong P, Delamarter RB, Dawson EG: Intervariability and intravariability of bone morphogenetic proteins in commercially available demineralized bone matrix products. Spine 2006;31: 1299-1306. Enzyme-linked immunosorbent assay was used to detect BMP-2, -4, and -7 in nine commercially available (off the shelf) DBM product formulations using three different manufacturers production lots of each DBM formulation. There is higher variability in concentration of BMPs among three different lots of the same DBM formulation than among different DBM formulations. Peterson B, Whang PG, Iglesias R, Wang JC, Lieberman JR: Osteoinductivity of commercially available demineralized bone matrix: Preparations in a spine fusion model. J Bone Joint Surg Am 2004;86-A:2243-2250. The efficacy of three different commercially available DBM products for inducing spinal fusion was compared using an athymic rat model. Cammisa FP Jr, Lowery G, Garfin SR, et al: Two-year fusion rate equivalency between Grafton DBM gel and autograft in posterolateral spine fusion: A prospective controlled trial employing a side-by-side comparison in the same patient. Spine 2004;29:660-666. A total of 120 patients underwent posterolateral spine fusion with pedicle screw fixation and bone grafting. Iliac crest autograft was implanted on one side of the spine and a Grafton DBM/autograft composite was implanted on the contralateral side in the same patient. Wozney JM, Rosen V: Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop Relat Res 1998;346:26-37. Morone MA, Boden SD, Martin G, et al: Gene expression during autograft lumbar spine fusion and the effect of bone morphogenetic protein-2. Clin Orthop Relat Res 1998;351:252-265. Jones AL, Bucholz RW, Bosse MJ, et al: BMP-2 Evaluation in Surgery for Tibial Trauma-Allgraft (BESTTALL) study group: Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects: A randomized, controlled trial. J Bone Joint Surg Am 2006;88:1431-1441. Adult patients (15 in each study arm) with a tibial diaphyseal fracture and a residual cortical defect were randomly assigned to receive either autogenous bone graft or allograft (cancellous bone chips) for staged reconstruction of the tibial defect. Patients in the allograft group also received an onlay application of 46. 42.

rhBMP-2 on an absorbable collagen sponge. Ten patients in the autograft group and 13 patients in the rhBMP-2/allograft group had healing without further intervention. McKay B, Sandhu HS: Use of recombinant human bone morphogenetic protein-2 in spinal fusion applications. Spine 2002;27:S66-S85. Boden SD, Kang J, Sandhu H, et al: Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: A prospective, randomized clinical pilot trial. Spine 2002;27:26622673. Glassman SD, Dimar JR, Carreon LY, et al: Initial fusion rates with recombinant human bone morphogenetic protein-2/compression resistant matrix and a hydroxyapatite and tricalcium phosphate/collagen carrier in posterolateral spinal fusion. Spine 2005;30:16941698. This article reports a prospective, randomized, unblinded study of iliac crest bone graft versus rhBMP-2/ compression-resistant matrix in a posterolateral instrumented fusion procedure. At 1 year after surgery, the mean fusion grade was 4.62 in the rhBMP-2/ compression-resistant matrix group versus 3.77 in the iliac crest bone graft group (P < 0.0023). Swiontkowski MF, Aro HT, Donell S, et al: Recombinant human bone morphogenetic protein-2 in open tibial fractures: A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am 2006;88:1258-1265. Two prospective, randomized clinical studies were conducted. A total of 510 patients with open tibial fractures were randomized to receive the control treatment (intramedullary nail fixation and routine soft-tissue management) or the control treatment and an absorbable collagen sponge impregnated with one of two concentrations of rhBMP-2. The rhBMP-2 implant was placed over the fracture at the time of definitive wound closure. Two subgroups were analyzed: (1) the 131 patients with a Gustilo-Anderson type-IIIA or IIIB open tibial fracture and (2) the 113 patients treated with reamed intramedullary nailing. The first subgroup demonstrated significant improvements in the rhBMP-2 group, with fewer bone grafting procedures (P = 0.0005), fewer patients requiring invasive secondary interventions (P = 0.0065), and a lower rate of infection (P = 0.0234), compared with the control group. Friedlaender GE, Perry CR, Cole JD, et al: Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001; 83(suppl 1):S151-S158. Vaccaro AR, Patel T, Fischgrund J, et al: A pilot study evaluating the safety and efficacy of OP-1 Putty (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis for degenerative spondylolisthesis. Spine 2004;29:1885-1892. Thirty-six patients with degenerative lumbar spondylolisthesis and symptoms of neurogenic claudication

36.

43.

44.

37.

45.

38.

1: Principles of Orthopaedics

39.

40.

41.

47.

American Academy of Orthopaedic Surgeons

Orthopaedic Knowledge Update 9

21

Section 1: Principles of Orthopaedics

were randomized (2:1) to either OP-1 Putty (Stryker, Kalamazoo, MI) (3.5 mg of OP-1 per side) or autogenous iliac crest bone graft for single-level uninstrumented posterolateral fusion following a decompressive laminectomy. Fourteen of 19 (74%) OP-1 Putty patients and 6 of 10 (60%) autograft patients achieved a successful posterolateral fusion, fulfilling all fusion criteria. 48. Vaccaro AR, Anderson DG, Patel T, et al: Comparison of OP-1 Putty (rhBMP-7) to iliac crest autograft for posterolateral lumbar arthrodesis: A minimum 2-year follow-up pilot study. Spine 2005;30:2709-2716. Efficacy data were tabulated for 27 patients at the 24month time point and an additional 4 patients (without

evaluatable 24-month results) at the 36-month time point. A successful posterolateral fusion was achieved in 11 of 20 (55%) OP-1 Putty patients and 4 of 10 (40%) autograft patients. 49. Alden TD, Pittman DD, Beres EJ, et al: Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy. J Neurosurg;1999:109-114. Boden SD, Titus L, Hair G, et al: Lumbar spine fusion by local gene therapy with a cDNA encoding a novel osteoinductive protein (LMP-1). Spine 1998;23:24862492.

50.

1: Principles of Orthopaedics

22

Orthopaedic Knowledge Update 9

American Academy of Orthopaedic Surgeons