Endochondral ossification and intramembranous ossifications are two types of ossification, process that results in the formation of bone tissue.

The two types of ossifications differ in the way new bone is formed.

In endochondral ossification, a cartilage is formed as a precursor on which new bone is laid down.

Intramembranous ossification is the direct laying down of bone into the primitive connective tissue (mesenchyme) and there is no intermediate cartilage involved.

Fractures treated by plaster applications heal by endochondral ossification whereas fractures treated by open reduction and rigid internal fixation heal by intramembranous ossification.

Enchondral ossification is responsible for the formation of long bones and their natural growth.

Intramembranous ossification is responsible for the formation of flat bones like skull bones and facial bones. Majority of clavicle bones are also formed by intramembranous ossification.

Ossification versus Calcification

Bone ossification is not same as calcification. Calcification is the laying of calcium-based salts and crystals within cells and tissue. Calcification is a normal part of ossification but it also occurs in many pathologies.

Endochondral Ossification

Endochondral ossification is essential for the formation of long bones [bones like femur which are longer than wide] and the ends of flat and irregular bones like ribs, vertebrae.

Endochondral ossification involved in natural growth and lengthening of bone. It is also involved in the natural healing of bone fractures.

The primary endochondral ossification is distinguished from intramembranous ossification is the fact that cartilage is present during endochondral ossification.

Formation of long bones has two centers of ossification.

The first site of ossification occurs in the primary center of ossification, which is in the middle of diaphysis [shaft] and secondary center of ossification which appear around birth at both ends of long bones [epiphysis].

Endochondral Ossification at Primary Ossification Center of Long Bone

• In long bones, bone tissue first appears in the diaphysis. Before this, the bone framework has been laid by cartilage
• Cartilage produced by chondrocytes is absorbed by osteoclasts beginning at the center of ossification
• Osteoblasts lay down the bone on the cartilaginous framework [bone replaces cartilage, cartilage is not converted to bone] leading to the formation of primary trabecular bone. [Note that final bone is medullary and will be formed later]
• Cartilage is progressively eroded and replaced by hardened bone, extending towards the epiphysis.
• Perichondrium layer surrounding the cartilage forms the periosteum which lays down bone to make a collar that encircles the outside of the bone.
• Osteoclasts, formed from macrophages, break down spongy bone to form the medullary (bone marrow) cavity.
• The osteoblasts are also responsible for appositional growth which increases the girth of the bone.  For appositional growth, the diameter of bones around the diaphysis grows by deposition of bone beneath the periosteum. From inside, the osteoclasts continue to resorb bone until its ultimate thickness is achieved. At this point the rate of formation on the outside and degradation from the inside is constant.

Endochondral Ossification in Secondary center of ossification: The Process of Bone Growth

The process is similar to primary ossification center. After secondary ossification center appears in the physis, the unossified cartilage left between the primary and secondary ossification centers is called the epiphyseal plate.

This cartilage plate is the key to form new cartilage, which is replaced by bone, a process that results in an increase in the length of the bone.  In simple terms, the cartilage plate continues lays down cartilage beneath and the process grows away from the center, leading to an increase in the length of the bone, layer by layer. Periods of growth spurts are associated with a faster formation.

The laid down cartilage is replaced by bone. After the puberty, the physeal plate is visible as the epiphyseal line.

At any given time there is a zone of new cartilage laid at the farther end of the bone followed by zone where new bone is being formed over the cartilage. There are different transitional zones in between.

A section of the end of growing bone reveals following histology –

Following zones are noted

Zone of resting cartilage

It contains normal, resting hyaline cartilage.

Zone of proliferation/cell columns

The chondrocytes undergo rapid mitosis, leading to proliferation and form distinctive looking stacks.

Zone of maturation/hypertrophy

The chondrocytes enlarge and begin to secrete alkaline phosphatase which triggers calcification

Zone of calcification

Chondrocytes die as they do not receive nutrition leaving cavities that will later become invaded by bone-forming cells.

Zone of ossification

Osteoprogenitor cells invade the area and differentiate into osteoblasts, which elaborate matrix that becomes calcified on the surface of calcified cartilage.

Sox-9 and PTHrP are the transcritption factors involved in bone growth

Addition of more extracellular matrix on the peripheral cartilage surface, which is accompanied by new chondroblasts that develop from the perichondrium results in an increase in thickness.

Endochondral Ossification in Fracture Healing

This is seen in casting, bracing and intramedullary nailing. These treatments allow for some motion at the fracture site.

Intramembranous ossification

Intramembranous ossification is a type of bone ossification where the bone tissue is created directly over the mesenchymal tissue [and not on cartilage as in endochondral ossification]. It occurs in healing of bone fractures and the initial formation of the flat bones of our skull. This process is also responsible for forming our jaw and clavicles, or collar bones.

Bone Formation by Intramembranous Ossification in Fracture

• The process is started by mesenchymal stem cells within mesenchyme or the medullary cavity of a bone fracture.
• A small group of mesenchymal stem cells replicate and form a cluster of cells, a nidus.
• Once a nidus has been formed the mesenchymal stem cells within it stop replicating.
• Morphological changes in the mesenchymal stem cells begin to occur and they turn into osteoprogenitor cell.
  • the cell body becomes larger and rounder
  • the long, thin cell processes vanish
  • Golgi apparatus and rough endoplasmic reticulum increase
• Osteoprogenitor cells also undergo a morphological process to turn into osteoblasts
  • Shape becomes more columnar
  • Amount of Golgi apparatus and rough endoplasmic reticulum increases.
• Osteoblasts create an extracellular matrix containing Type-I collagen [ osteoid.]. Some of the osteoblasts become incorporated within the osteoid to become osteocytes.
• Mineralization occurs resulting in bone tissue and bone spicules
• Further secretion of osteoid increases the size of spicules which fuse with each other and become trabeculae.
• With continuous growth, trabeculae become interconnected and woven bone is formed.
  • The term primary spongiosa is also used to refer to the initial trabecular network.
• The periosteum is formed around the trabeculae
• Osteogenic cells that originate from the periosteum increase appositional growth and a bone collar is formed.

Eventually, woven bone is replaced by lamellar bone.

Following is a very good visual explanation of endochondral ossification.