Bone Injury and Fracture Healing

Connor R. LaRose

Carlos A. Guanche

Fracture healing involves multiple orchestrated events that are intimately linked to each other (25). The goal of fracture healing is to restore the bone injury to the preinjury biologic and biomechanical state. To accomplish this task, the cellular content of bone and the ability of such cells to produce extracellular matrix and structure are altered.

BONE ANATOMY (5,6,9)

Bone Cells

Osteoprogenitor Cells

Present on all bone surfaces, make up the deep layer of the periosteum and the endosteum, and can migrate from surrounding tissue.
Osteoprogenitor cells are marrow stromal cells that differentiate into osteoblasts (9).
The periosteum contains two layers: an outer layer of fibrous tissue and an inner layer (cambium) that contains cells capable of becoming osteoblasts.
The endosteum is a single layer of osteogenic cells lacking a fibrous component.

Osteoblasts

Mature, metabolically active bone-forming cells.
- Secrete osteoid, the unmineralized matrix that subsequently undergoes mineralization.
- Some osteoblasts are converted into osteocytes, whereas others remain on the surfaces of bone as lining cells.
- Play a role in the activation of bone resorption by osteoclasts.

Osteocytes

Mature osteoblasts trapped within the bone matrix.
Form a network of cytoplasmic processes extending through cylindrical canaliculi to blood vessels and other osteocytes.
Involved in extracellular calcium and phosphorus homeostasis.
Act as in a paracrine function on active osteoblasts.

Osteoclasts

Multinucleated bone-resorbing cells controlled by hormonal and cellular mechanisms.
Differentiate from hematopoietic cells from the monocyte/macrophage cell lines (9).
Function in groups termed cutting cones that attach to bare bone surfaces and dissolve inorganic and organic matrices of bone and calcified cartilage through the use of hydrolytic enzymes.
Formation of ruffled border at bone-osteoclast interface leads to breakdown of organic and inorganic components (9).
Process results in the formation of shallow pits on the bone surface called Howship’s lacunae (5).

Types of Bone (6)

Woven Bone (Primary Bone)

Primary bone formed during embryonic development, during fracture healing, and in some pathologic states such as hyperparathyroidism and Paget’s disease (5,6).
Composed of randomly arranged collagen bundles and irregularly shaped vascular spaces.
Higher cellularity than lamellar bone and is not organized according to mechanical stress.
Weaker and more easily deformed compared to lamellar bone secondary to irregular collagen orientation.

Lamellar Bone (Secondary Bone)

Highly organized with densely packed collagen fibrils that are organized according to stress lines.
Behaves anisotropically; the mechanical properties of the bone change depending on the direction of the applied force.
Woven bone present at a fracture site must be eventually replaced by lamellar bone to restore the normal mechanical properties of bone.

Cortical Bone

Dense compact bone that is primarily responsible for load bearing in the diaphysis of long bones.
Remodeled from woven bone by means of vascular channels that invade the embryonic bone from its periosteal and endosteal surfaces.
The primary structural unit of cortical bone is an osteon, also known as a Haversian system.
- Consists of cylindrical-shaped lamellar bone that surrounds longitudinally oriented vascular channels called Haversian canals.
- Horizontally oriented canals (Volkmann) connect adjacent osteons.
- Mechanical strength of cortical bone is dependent on the concentration of the osteons.

Cancellous Bone (Trabecular)

Lies between cortical bone surfaces and consists of a network of honeycombed interstices containing hematopoietic elements and bony trabeculae.
Structurally important at epiphyseal-metaphyseal ends of long bone. Allows for absorption of loads across synovial joints.
Trabeculae are oriented perpendicular to external forces to provide structural support (48).

BONE BIOCHEMISTRY (9)

Bone is composed of organic matrix and mineral matrix.
- Mineral matrix: Dry bone is made up of hydroxyapatite and tricalcium phosphate (65%-70% of the weight). Responsible for the compressive strength of bone.
- Organic matrix: 90% type 1 collagen, 5% other collagen types, noncollagenous material, and growth factors (30%-35% of the weight).
- Osteoid: Unmineralized organic matrix secreted by osteoblasts; composed of 90% type I collagen and 10% ground substance (noncollagenous proteins, glycoproteins proteoglycans, peptides, carbohydrates, and lipids). Mineralization of this substance by inorganic mineral salts provides bone with its strength and rigidity.
- Inorganic bone contents: Primarily calcium phosphate and calcium carbonate with small quantities of magnesium, chloride, and sodium. Mineral crystals form hydroxyapatite, an orderly precipitate around the collagen fibers of the osteoid.

Regulators of Bone Metabolism (1,4,44)

Three of the calcitropic hormones that have the most effect on metabolism are parathyroid hormone, vitamin D, and calcitonin.
- Parathyroid hormone is an amino acid made and secreted from the chief cells of the parathyroid gland. It is secreted in response to low plasma calcium. It directly activates osteoblasts to secrete receptor activator of nuclear factor κ-B ligand (RANKL), which stimulates osteoclastic development.
- Vitamin D stimulates intestinal and renal calcium-binding proteins and facilitates active calcium transport.
- Calcitonin is secreted by the parafollicular cells of the thyroid gland in response to rising plasma calcium level. Calcitonin serves to inhibit calcium-dependent cellular metabolic activity.
Miscellaneous proteins: Released from platelets, macrophages, and fibroblasts. Cause healing bone to vascularize, solidify, incorporate, and function mechanically. Induce mesenchymal-derived cells such as monocytes and fibroblasts to migrate, proliferate, and differentiate into bone cells (23,37).
Proteins that enhance bone healing include the bone morphogenic proteins (BMPs), insulin-like growth factors, transforming growth factors (TGFs), platelet-derived growth factor, and fibroblast growth factor, among others (10,14,50).

Bone Morphogenic Proteins (15,17)

Unique group of biologically active proteins that belong to the TGF-β superfamily.
Over 20 different BMPs have been discovered, but only BMP-2, -4, -6, -7, and -9 have been shown to have osteogenic properties.
In vivo, different BMPs act at different times and at differing concentrations during bone formation.
Currently BMP-2 and BMP-7 have been approved for use in treatment of tibial fractures and anterior spinal fusion (2,15,16,17).

BONE-HEALING PROCESS

Fracture healing restores the tissue to its original physical and mechanical properties and is influenced by a variety of systemic and local factors (26,39). Healing occurs in three distinct but overlapping stages (36,40).

Inflammatory Stage

A hematoma develops within the fracture site during the first few hours and days. Inflammatory cells and fibroblasts infiltrate the bone under prostaglandin mediation. This results in the formation of granulation tissue, ingrowth of vascular tissue, and migration of mesenchymal cells (4).
Osteoblast proliferation occurs at the fracture site from the surrounding osteoprogenitor cells.
Anti-inflammatory or cytotoxic medications during this first week are particularly detrimental to the initial inflammatory response to healing (41).

Repair Stage