Bone Formation, Development, and Repair

1. Bone Formation

In the early stages of human development, the skeleton consists of fibrous membranes and hyaline cartilage. By the sixth or seventh week of life in the womb, the actual process of bone development, ossification (osteogenesis), begins. There are two pathways that osteogenesis can take:

• Intramembranous Ossification
• Endochondral Ossification

Bone is a replacement tissue; that is, it uses a model tissue on which to lay down its mineral matrix. For skeletal development, the most common template is cartilage. During development, a framework is laid down that determines where bones will form. This framework is a flexible, semi-solid matrix produced by chondroblasts, which are the cells from cartilage that produce the extracellular matrix. As the matrix surrounds and isolates chondroblasts, they are called chondrocytes.

key concept

Unlike most connective tissues, cartilage is avascular, meaning that it has no blood vessels supplying nutrients and removing metabolic wastes. All of these functions are carried on by diffusion through the matrix. This is why damaged cartilage does not repair itself as readily as most tissues do.

Up through childhood growth and development, bone forms from a cartilage model. By birth, most of the cartilage has been replaced with bone. Some additional cartilage will be replaced throughout childhood, and some cartilage remains in the adult skeleton forever.

term to know

Ossification

The process of bone formation.

1a. Intramembranous Ossification

During intramembranous ossification, compact and spongy bone develops directly from sheets of undifferentiated connective tissue (intra, inside; membranous, membrane). The flat bones of the face, most of the skull bones, and the collarbones (clavicles) are formed via intramembranous ossification. These bones form in four steps.

step by step

1. Form ossification center.
The cells in the embryonic skeleton gather together and begin to differentiate (specialize). Some will differentiate into capillaries, whereas others will become osteogenic cells and then osteoblasts. Although they will ultimately be spread out by the formation of bone tissue, early osteoblasts appear in a cluster called an ossification center.


2. Form osteocytes.
The osteoblasts secrete osteoid, uncalcified bone matrix that calcifies (hardens) within a few days as mineral salts are deposited on it and thereby entrapping the osteoblasts within. Once entrapped, the osteoblasts become osteocytes. As osteoblasts transform into osteocytes, osteogenic cells in the surrounding connective tissue differentiate into new osteoblasts.


3. Form trabeculae and periosteum.
Osteoid (unmineralized bone matrix) secreted around the capillaries results in a trabecular matrix, whereas osteoblasts on the surface of the spongy bone become the periosteum.


4. Form compact bone and red bone marrow.
The periosteum then creates a protective layer of compact bone superficial to the trabecular bone. The trabecular bone crowds nearby blood vessels, which eventually condense into red bone marrow.

Intramembranous ossification begins in utero (in the uterus) during early development and continues on into adolescence. At birth, the skull and clavicles are not fully ossified nor are the sutures of the skull closed. This allows the skull and shoulders to deform during passage through the birth canal. The last bones to ossify by intramembranous ossification are the flat bones of the face, which reach their adult size at the end of the adolescent growth spurt.

terms to know

Intramembranous Ossification

The process of bone formation from undifferentiated connective tissue.

Osteoid

Uncalcified bone matrix produced and secreted by osteoblasts.

1b. Endochondral Ossification

In endochondral ossification, bone develops by replacing hyaline cartilage (endo, inside; chondral, cartilage). Cartilage does not become bone but instead serves as a template to be completely replaced by new bone. Endochondral ossification takes much longer than intramembranous ossification. Bones at the base of the skull and long bones form via endochondral ossification. These bones form in four steps.

step by step

1. Form chondrocytes and perichondrium.
In a long bone, for example, at about 6 to 8 weeks after conception, some of the cells differentiate into chondrocytes that form the early skeleton. Soon after, the perichondrium, a membrane that covers the cartilage (peri, around), appears.


2. Form medullary cavity.
As more matrix is produced, the chondrocytes in the center of the tissue grow in size. As the matrix calcifies, nutrients can no longer reach the chondrocytes. This results in their death and the disintegration of the surrounding cartilage. These enlarging spaces eventually combine to become the medullary cavity.


3. Form primary ossification center.
As the cartilage grows, blood vessels penetrate it, initiating two transformations. First, the perichondrium becomes the bone-producing periosteum. Here, osteogenic cells transported in by the blood vessels turn into osteoblasts and form a periosteal collar of compact bone around the cartilage of the diaphysis. Second, by the second or third month of life in the womb, bone production ramps up deep inside, forming the primary ossification center. This region of ossification expands to convert the diaphysis to osseous (bone) tissue and reaches out to both epiphyses (singular, epiphysis).


4. Form secondary ossification center.
After birth, the same sequence of events (matrix mineralization, death of chondrocytes, invasion of blood vessels, and seeding with osteogenic cells that become osteoblasts) occurs in the epiphyseal region as what is called the secondary ossification center. Cartilage will then remain in two locations. Between the diaphysis and epiphysis, the epiphyseal cartilage or plate is responsible for bone growth in length but converts to bone tissue during puberty. At the joint (articular) surface, articular cartilage smooths joint movement for life or until damaged or diseased.

terms to know

Endochondral Ossification

The process of bone formation by replacement of hyaline cartilage.

Perichondrium

A membrane that covers the surface of cartilage.

Primary Ossification Center

The initial site of osteogenesis during endochondral ossification, located in the diaphysis.

Secondary Ossification Center

The second site of osteogenesis during endochondral ossification, located in the future epiphyses.

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2. Long Bone Growth

Long bones continue to lengthen, potentially until adolescence, through the addition of bone tissue at the epiphyseal plate. They also increase in width through appositional growth.

2a. Lengthening of Long Bones

The epiphyseal (growth) plate is responsible for the longitudinal growth (growth in length) of a long bone, called interstitial growth. Chondrocytes on the epiphyseal side of the epiphyseal plate divide; one cell remains undifferentiated near the epiphysis, and one cell moves toward the diaphysis. The cells, which are pushed from the epiphysis, mature and are destroyed by calcification. This process replaces cartilage with bone on the diaphyseal side of the plate, resulting in a lengthening of the bone. The growth plate zones that facilitate interstitial growth are shown in the figure below.

Long bones stop growing at around the age of 18 in females and the age of 21 in males in a process called epiphyseal plate closure. During this process, cartilage cells stop dividing and all of the cartilage is replaced by bone. The epiphyseal plate fades, leaving a structure called the epiphyseal line or epiphyseal remnant, and the epiphysis and diaphysis fuse.

An X-ray of this region shows the presence of an epiphyseal plate or line and can be used to determine whether a bone is done growing or not, as well as its approximate age.

term to know

Interstitial Growth

Growth of a long bone in length.

2b. Thickening of Long Bones

While long bones are increasing in length, they are also increasing in diameter, called appositional growth. Growth in diameter can continue even after longitudinal growth ceases.

Osteoclasts resorb old bone that lines the medullary cavity, whereas osteoblasts, via intramembranous ossification, produce new bone tissue beneath the periosteum. The erosion of old bone along the medullary cavity and the deposition of new bone beneath the periosteum not only increase the diameter of the diaphysis but also increase the diameter of the medullary cavity. This process is called modeling.

terms to know

Appositional Growth

Growth of a long bone in width.

Modeling

The process, during bone growth, by which bone is resorbed on one surface of a bone and deposited on another.

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3. Bone Remodeling and Repair

Bone modeling primarily takes place during a bone’s growth—during development. However, in adult life, bone undergoes remodeling, in which resorption of old or damaged bone takes place on the same surface where osteoblasts lay new bone to replace that which is resorbed. Injury, exercise, and other activities lead to remodeling. Even without injury or exercise, approximately 5% to 10% of the skeleton is remodeled annually just by destroying old bone and renewing it with fresh bone.

term to know

Remodeling

The process, after bone growth, by which bone is resorbed and deposited on the same surface.

3a. Bone Fractures

A fracture is a broken bone. Fractures occur when pressure is applied to a bone that the bone tissue cannot withstand. Recall that osseous (bone) tissue is composed of collagen for strength and inorganic salts for hardness. Once fractured, a bone will heal whether or not it is reset in its anatomical position. However, if the bone is not reset correctly, the healing process will keep the bone in its deformed position.

When a broken bone is manipulated and set into its natural position without surgery, the procedure is called a closed reduction. Open reduction requires surgery to expose the fracture and reset the bone. Although some fractures can be minor, others are quite severe and result in grave complications.

EXAMPLE

A fractured diaphysis of the femur (large upper leg bone) has the potential to release fat globules into the bloodstream. These can become lodged in the blood vessels of the lungs, leading to respiratory distress and, if not treated quickly, death.

Fractures are classified by their complexity, location, and other features. The table below outlines common types of fractures. Some fractures may be described using more than one term because they may have features of more than one type (i.e., an open transverse fracture).

Type of fracture	Description
Closed (or Simple) Fracture	A fracture in which the skin remains intact
Open (or Compound) Fracture	A fracture in which at least one end of the broken bone tears through the skin; carries a high risk of infection
Transverse Fracture	A fracture that occurs straight across the bone, perpendicular to the long axis of the bone
Spiral Fracture	Bone segments are pulled apart as a result of a twisting motion
Comminuted Fracture	Several breaks resulting in many small pieces between two large segments
Impacted Fracture	One fragment is driven into the other, usually as a result of compression
Greenstick Fracture	A partial fracture in which only one side of the bone is broken
Oblique Fracture	A fracture that occurs at an angle that is not 90 degrees

term to know

Fracture

A broken bone.

3b. Bone Repair

Recall that osseous (bone) tissue contains a significant number of blood vessels. Therefore, when a fracture occurs, blood flows from any torn blood vessel, whether in the periosteum, osteons, and/or medullary cavity. This blood allows for a faster repair process by providing nutrients, cells, and waste removal. The process of repairing a bone occurs in four steps or stages.

step by step

1. Form a fracture hematoma.
As the blood pools in the new space, it begins to clot, and about 6 to 8 hours after the fracture, the clotting blood has formed a fracture hematoma. The disruption of blood flow to the bone results in the death of bone cells around the fracture.


2. Form an internal and external callus.
Within about 48 hours after the fracture, the cells in the region of the fracture will fill in the space with temporary materials. On the inside, chondrocytes from the endosteum create an internal callus (plural, calli) by secreting a fibrocartilaginous matrix between the two ends of the broken bone. Meanwhile, the periosteal chondrocytes and osteoblasts create an external callus of hyaline cartilage and bone, respectively, around the outside of the break. This stabilizes the fracture.


3. Replace calli with spongy bone.
Over the next several weeks, osteoclasts resorb the dead bone. Then, osteogenic cells become active, divide, and differentiate into osteoblasts. The cartilage in the calli is replaced by trabecular bone via endochondral ossification.


4. Replace spongy bone with compact bone.
Eventually, the internal and external calli unite, compact bone replaces spongy bone at the outer margins of the fracture, and healing is complete. A slight swelling may remain on the outer surface of the bone, but quite often, over time that region undergoes remodeling, and no external evidence of the fracture remains.

terms to know

Fracture Hematoma

A blood clot that forms at a broken bone.

Internal Callus

A temporary cartilage filling formed between two ends of a broken bone (plural, calli).

External Callus

A temporary cartilage and spongy bone filling formed around the outside of a broken bone (plural, calli).