Chapter 5 - Bone Development, Growth and Structure
 
Ossification
     Bone appears in the 6-week-old embryo and growth of bone continues till about 25 years old. Bone formation may still occur but involves remodeling. The process of bone formation is called ossification. and there are two types of ossification: intramembranous ossification where bone develops from mesenchyme or fibrous connective tissue; and endochondral ossification where bone develops from a pre-existing cartilage model. 
Intramembranous Ossification a.k.a. dermal ossification
     Intramembranous ossification occurs in the deeper layers of the dermis where mesenchymal cells in embryonic or fibrous connective tissue become osteoblasts that produce bone.
 
  Process of intramembranous ossification:
  Step 1.
     Intramembranous ossification begins when mesenchymal cells migrate and form aggregations in specific areas called ossification centers. The mesenchymal cells differentiate into osteoblasts. The osteoblasts produce bone matrix which undergoes calcification. As the osteoblasts become encased in bone matrix they become osteocytes.
  Step 2.
     Bone grows from the ossification center in linear extensions called spicules. Blood vessels grow and branch around the spicules to support the bone tissue.
  Step 3.
     The continued growth at multiple ossifications centers results in the enlargement and fusion of spicules in the trabecular network characteristic of spongy bone. Further remodeling produces the spongy bone, marrow cavities and compact bone characteristic of mature bone.
 
  Process of endochondral ossification
     Endochondral ossification occurs in a cartilage model of the bone that appears first in the developing embryo. The cartilage model approximates the shape of the future bone and grows by both interstitial and appositional growth.
  Step 1.
     The chondrocytes in the center of the cartilage model become larger and the surrounding cartilage matrix becomes calcified. These chondrocytes undergo programmed death leaving behind cavities within the cartilage matrix.
  Step 2.
     The perichondrium of the cartilage model becomes transformed into a periosteum as an osteogenic layer forms. The periosteum produces a thin collar of bone around the shaft of the cartilage model.
  Step 3.
       Blood vessels and osteoprogenitor cells from the periosteum migrate into the cavities within the calcified cartilage matrix. The calcified cartilage breaks down but before doing so provides a surface on which osteoblasts can produce spongy bone. This then becomes a primary ossification center. 
  Step 4.
     As osteogenesis continues in the primary ossification center, a cavity results as the bone is remodeled. This central cavity is called the marrow cavity. Further growth involves an increase in both the length and diameter of the bone.
     Increasing the length of the developing bone
       Before describing how bones increase in length some terminology needs to be introduced. The shaft of the long bone is called the diaphysis and the two expanded ends are called epiphyses (each is called an epiphysis). The flared portion between the epiphysis and the diaphysis is called the metaphysis. Growth in the length of bone occurs in the epiphysis in a piece of cartilage called the epiphyseal plate.
  Step 5.
     Secondary ossification centers appear in the epiphyses in a manner similar to that described above for the primary ossification center.
  Step 6.
     As ossification proceeds, the epiphyses become filled with spongy bone and only a thin piece of hyaline cartilage remains on the articular surface as articular cartilage. A thin plate of cartilage, the epiphyseal plate, now separate the bone of the epiphyses from that of the diaphysis. Growth in the length of the bone occurs at the epiphyseal plate as is evidenced by the appearance of zones within the cartilage. Proceeding from the epiphyseal side to the the diaphyseal side the zones are:
  Zone of reserve or resting cartilage
     The chondrocytes here exhibit no division or active matrix production.
  Zone of proliferation
     The chondrocytes undergo cell division and arrange themselves in distinct columns that are parallel to the direction of growth.
  Zone of hypertrophy
     The chondrocytes enlarge and compress the cartilage matrix surrounding them.
  Zone of calcification
     The enlarged cells begin to degenerate as the matrix becomes calcified.
  Zone of resorption (a.k.a. ossification)
     The cavities left by the dead chondrocytes are invaded by blood vessels that bring osteoprogenitor cells with them. Bone is produced on the surface of the calcified cartilage as it undergoes resorption.
  Step 7.
     The bone increases in length as long as the rate of cartilage production equals the rate by which it is replaced by bone. As the bone matures the rate of bone production "catches up" with the rate of cartilage production and the cartilage that was the epiphyseal plate is replaced by an epiphyseal line.
 
     Increasing the diameter of the developing bone
       The diameter of bone increases by appositional growth. Osteoblasts in the cellular layer of the periosteum add success layers of bone called circumferential lamellae. At the same time, osteoclasts on the interior surface resorb bone and widen the marrow cavity. The final result is an increase in both the diameter and marrow cavity of the bone.