Normal and Abnormal Fracture Healing
Francis Y. Lee, MD, PhD, Hon MBA, FAAOS
Hicham Drissi, PhD
Dr. Lee or an immediate family member serves as a paid consultant to or is an employee of L&J Bio and has received research or institutional support from Musculoskeletal Transplant Foundation, National Institutes of Health (NIAMS & NICHD), and OREF. Dr. Drissi or an immediate family member serves as a paid consultant to or is an employee of Merck and has received research or institutional support from Merck.
ABSTRACT
Normal fracture healing means restoration of bone continuity with respect to structural, mechanical, and biochemical integrity. Fracture healing process is a cascade of well-orchestrated cellular events consisting of acute injury (inflammatory) phase, recruitment of reparative progenitor cells for callus formation, tissue transition from callus to mature bone, and remodeling. Each fracture healing stage is affected by host factors such as aging, diabetes, endocrinopathies, infection, drugs, smoking, and mechanical stability during fracture healing. Rigorous modern scientific research has identified specific causes for impaired fracture healing.
Keywords: delayed union; fracture healing; nonunion; pathologic fractures
Introduction
Fracture healing is not always unfailing. Impaired fracture healing remains a serious clinical dilemma. A significant percentage of surgically and nonsurgically managed fractures are associated with delayed union and nonunions. A tremendous effort was geared toward understanding the mechanisms of successful and failed fracture healing using preclinical models. The use of rodents enabled the scientific community to get at the mechanistic aspects of fracture healing and at such patient factors as metabolic diseases, aging, infection, genetics, pain, and behavior as well as functional outcome measures and mechanics. Learning from normal fracture healing, orthopaedic surgeons are now in a position to rescue impaired fracture healing by rectifying dysregulated cellular events secondary to pathologic conditions. It is important to discuss fundamentals of bone repair using long bone fractures and in the context of several risk factors of impaired healing.
Normal Fracture Healing
Bone has a remarkable capacity for regeneration, and in most cases, bone heals without complications.1 Fracture healing is a complex process that involves inputs from many different tissues and cell populations. The nature of the fracture and clinical management will determine how a fracture will heal. Normal fracture healing can progress through (1) primary intramembranous (direct) or (2) secondary healing, which involves both intramembranous and endochondral (indirect) processes. Primary bone repair requires accurate anatomic reduction and rigid fixation, typically with plate and screws. Secondary fracture healing is a common mechanism through which most bones heal clinically after stabilization with casting or intramedullary fixation.
Biology of Primary Bone Healing
Primary healing progresses through intramembranous ossification, which occurs through contact healing or gap healing. During this process, new bone is directly deposited at the fracture site and does not require a cartilaginous intermediate. These mechanisms are discussed in the next paragraphs.
Contact Healing
When anatomic reduction and rigid fixation are achieved, contact healing can take place.
The distance between the two ends of the fracture site should be less than 0.01 mm and the interfragmentary strain less than 2%.2 Cutting cones, a tunnel lined by leading osteoclasts and following osteoblasts, are formed at the end of osteons. At the tip of the osteons, osteoclasts cross the fracture line and generate longitudinal cavities at a rate of 50 to 100 µm/d.1 Osteoblasts
then form bone to fill these cavities and bony union is achieved. The restoration of the haversian system and the generation of bony union happen simultaneously, which is a characteristic of contact primary bone healing process.1,3 Ultimately, the bridging osteons mature into lamellar bone and bone healing is achieved without the formation of a periosteal callus.
then form bone to fill these cavities and bony union is achieved. The restoration of the haversian system and the generation of bony union happen simultaneously, which is a characteristic of contact primary bone healing process.1,3 Ultimately, the bridging osteons mature into lamellar bone and bone healing is achieved without the formation of a periosteal callus.
Gap Healing
For this type of fracture healing to occur, rigid fixation must be achieved and the gap between the two bony fragments should be less than 1 mm.3 The gap between the fractured ends is filled with lamellar bone that is oriented perpendicular to the long axis and a secondary osteonal reconstruction is necessary.1 The lamellar bone being perpendicular to the long axis is mechanically weak. Remodeling of this bone through a similar process observed during contact healing takes place after 3 to 8 weeks. This will fully restore the anatomic and biomechanical properties of the bone.2
Biology of Secondary Fracture Healing
Secondary fracture healing progresses through a series of sequential yet overlapping events (Figure 1). These events or stages have been broadly grouped into a four-phase or three-phase model of secondary bone repair. In the four-phase model, an initial hematoma will form that will be replaced by a soft cartilaginous callus. This soft callus undergoes ossification to form a hard bony callus that is remodeled in a final phase to restitute the initial geometry of the broken bone before fracture.1 The three-phase model is defined as having a reactive, repair, and remodeling phase. The reactive phase occurs immediately following trauma and is driven by the local disruption of blood vessels and surrounding soft tissue. This localized tissue injury promotes the formation of a hematoma that eventually coagulates to serve as the template for callus formation. Simultaneously, this initiates an acute inflammatory response that recruits immune cells to the fracture site. These cells invade the hematoma where they facilitate the removal of dead cells and debris as well as secrete cytokines and chemokines. These factors are responsible for recruiting immunosuppressive mesenchymal progenitor cells from the periosteum, bone marrow, and systemic circulation that ultimately leads to resolution of inflammation and initiation of the repair phase. During the repair phase, mesenchymal stem cells undergo differentiation into chondrocytes, which lead to the formation of the soft cartilaginous callus. This avascular callus undergoes vascularization that facilitates the transition of the soft callus into hard bony callus. The remodeling phase requires the activities of osteoclasts to resorb the hard bony callus consisting of woven bone and osteoblasts to deposit lamellar bone. At the conclusion of this phase, the original geometry (shape and architecture) of the bone is restored with no outward signs that a fracture has occurred (ie, no scarring).
 Figure 1 Schematic representation of fracture repair. On fracture induction (middiaphyseal break under Frax), hematoma formation and inflammation occur shortly after (in red; first 3 weeks in human adults) and within days (week 4 in humans and first week in C57/bl6 mice); a soft cartilaginous callus will initiate bridging. The soft callus will be invaded with vessels and cartilage is progressively replaced by bone to form a more mechanically stable bony callus (up to 12 months following fracture in humans and 2 to 3 weeks in C57/bl6 mice). The last phase of healing involved callus remodeling to recover the initial geometry of the long bone (remodeling phase around 6 months in humans and 2 to 3 weeks in C57/bl6 mice). |
The Reactive Phase
Immediately following trauma there is rupture of blood vessels inside and around the fracture site, creating a local hematoma. The hematoma will serve as a scaffold for different inflammatory cells, cytokines, and chemokines
(eg, interleukin [IL]-1, IL-6, CCL2, and others) to initiate the inflammatory cascade.4 Various immune cells including peripheral blood mononuclear cells, monocytes, and macrophages infiltrate the fracture site. Macrophages are polarized to the M1 phenotype. Peripheral blood mononuclear cells and macrophages clear the area of dead cells and debris and the process shifts to the resolution of inflammation. In this phase, inflammation and the synthesis of proinflammatory mediators are both reduced. For the resolution of acute inflammation, macrophages are polarized to the M2 phenotype and begin to secrete anti-inflammatory cytokines (eg, IL-4, IL-10, and IL-13). Mesenchymal stem cells primarily from the bone marrow and periosteum are also attracted to the fracture site by cytokines such as tumor necrosis factor alpha5 and stromal cell-derived factor 1.6
(eg, interleukin [IL]-1, IL-6, CCL2, and others) to initiate the inflammatory cascade.4 Various immune cells including peripheral blood mononuclear cells, monocytes, and macrophages infiltrate the fracture site. Macrophages are polarized to the M1 phenotype. Peripheral blood mononuclear cells and macrophages clear the area of dead cells and debris and the process shifts to the resolution of inflammation. In this phase, inflammation and the synthesis of proinflammatory mediators are both reduced. For the resolution of acute inflammation, macrophages are polarized to the M2 phenotype and begin to secrete anti-inflammatory cytokines (eg, IL-4, IL-10, and IL-13). Mesenchymal stem cells primarily from the bone marrow and periosteum are also attracted to the fracture site by cytokines such as tumor necrosis factor alpha5 and stromal cell-derived factor 1.6
The Repair Phase
After the formation of the primary hematoma, a fibrin-rich granulation tissue forms.1 This tissue serves as the initial template for the callus that will undergo endochondral bone formation at the fracture site. Intramembranous ossification also occurs during this phase; however, this new process primarily occurs proximal and distal to the fracture site. During endochondral ossification, the mesenchymal stem cells from the bone marrow and periosteum differentiate into chondrocytes, which will facilitate the formation of the soft cartilaginous callus. The degree of micromotion at the fracture site will strongly influence the size of the soft callus. The soft callus is avascular initially and undergoes vascular invasion as the chondrocytes undergo hypertrophy.7 This permits the transition of the soft callus into a hard callus as cartilaginous callus is resorbed and is replaced by bone by osteoblasts or possibly by transdifferentiating hypertrophic chondrocytes. The fracture becomes semirigid with the bridging of this central hard callus.4 Further mineralization of the cartilaginous callus will increase the mechanical stability of the callus and ultimately the formation of hard callus.4
The Remodeling Phase
After the formation of a hard callus, a resorptive phase is initiated, which will replace the hard callus with a lamellar bone structure with a central medullary cavity.4 The remodeling is achieved by the simultaneous resorptive activity of osteoclasts and deposition of bone by osteoblasts.1 The external callus is replaced by lamellar bone and the internal callus reestablishes the medullary canal in the case of diaphyseal bone fracture.1 The fracture is considered healed when the central medullary canal is reestablished and cortical bridging has been achieved.
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