Histogenesis, Remodeling, Growth, and Repair

Primary bone. The first bone tissue appears during the formation of new bone or in the repair of fractures is termed primary bone, or woven bone. This immature bone, which is always spongy, is later replaced by secondary bone except near the skull sutures and in alveolar bone of the mandible and maxilla. Its collagen fibers do not form concentric rings but, rather, exhibit an irregular "woven" appearance. It is less mineralized than secondary bone, making it more radiolucent (penetrable by X-rays), and it has a higher osteocyte-to-matrix ratio. Primary bone can form by either intramembranous or endochondral bone formation.

Intramembranous bone formation occurs within membrane-like mesenchymal condensations. The cells in such connective tissue membranes differentiate into osteoblasts and begin to synthesize and secrete osteoid, which later becomes mineralized. This initial site of bone formation is termed the primary ossification center. The osteoblasts surround themselves with bone matrix, forming spicules that eventually fuse into a spongy lattice of primary bone. The mesenchyme between the spicules may participate in bone marrow development. Only a few human bones form entirely in this way, most of these are flat and are called membrane bones. Membrane bones of the skull are the frontal and parietal bones, the mandible, and the maxilla. The term "membrane bone" also refers to the tissue type formed by this mechanism. Membrane bone also forms parts of other bones, such as the temporal and occipital bones of the skull and the periosteal bone collar of endochondral bones.

Endochondral bone formation involves the replacement of cartilage by bone and occurs in all except membrane bones. Basic steps in the formation of an endochondral bone:

1. Cartilage model. In the embryo, a hyaline cartilage model, which resembles the bone to be formed, is laid down.

2. The periosteal bone collar. Capillaries penetrate the perichondrium, and mesenchymal cells on its inner surface become osteoprogenitor cells. Some of these differentiate into osteoblasts and secrete bone matrix, creating primary bone spicules just inside the perichondrium (now the periosteum). The spicules eventually fuse to form a thin periosteal bone collar of membrane bone around the cartilage model.

3. Proliferation. While the periosteal bone collar is forming, structural and functional changes begin in the cartilage model. The chondrocytes near the collar undergo rapid proliferation, forming long columns (isogenous groups) of flattened cells oriented parallel to the long axis of the bone.

4. Hypertrophy. The chondrocytes hypertrophy rapidly into large, rounded cells that are not separated by matrix. The result is tube-like superlacunae filled with columns of hypertrophic chondrocytes, which secrete type X collagen.

5. Calcification. As hypertrophy progresses, the long strips of cartilage matrix between the tubular cavities begin to calcify. Thus oxygen, nutrients, and cellular wastes can no longer diffuse through the matrix, and the hypertrophic chondrocytes die.

6. Formation of the primary marrow cavity. Dead chondrocytes and part of the calcified cartilage matrix are removed by chondroclasts (large, multinucleated cells resembling osteoclasts). Tunnels at the center of the developing bone stimulate proliferation and hypertrophy of chondrocytes and enlarged by chondroclasts, become the bone's primary marrow cavity.

7. The periosteal bud is a small cluster of blood vessels and perivascular tissue from the periosteum that penetrates the primary marrow cavity. This bud and its branches invade the tunnels left by the dead chondrocytes. Osteoprogenitor cells and bone marrow stem cells, delivered by the invading blood vessels, are deposited on the surface of the calcified cartilage matrix.

8. Ossification. This is term whose interpretation requires attention to context. In its broadest sense, ossification is synonymous with bone formation.

Here, in a more restricted connotation, it refers to the final steps in the process, including the deposition of osteoid followed by mineralization. The osteoprogenitor cells divide and differentiate into osteoblasts, which deposit primary bone on the surface of the calcified cartilage matrix strips. The primary bone and the residual calcified cartilage are later resorbed and replaced by secondary bone.

Ossification centers. The above steps may occur more than once in forming a bone. In long bones, the process occurs first near the middle of the diaphysis, forming the primary ossification center. The secondary ossification centers form later, by the same process, in the epiphyses. The region between a primary and a secondary ossification center is termed a metaphysis. The ossification centers enlarge until all that is left between them is a thin plate with resting cartilage at its center, the epiphyseal plate. In humans, the first bone to ossify is the clavicle.

5 overlapping zones characterize the microscopic structure of the metaphyses of developing endochondral bones:

1. The zone of resting cartilage is composed of typical hyaline cartilage and is farthest from the primary marrow cavity.

2. The zone of proliferation contains columns (isogenous groups) of flattened chondrocytes.

3. In the zone of hypertrophy, the chondrocytes in the columns are enlarged and rounded.

4. The zone of calcification is characterized by a more basophilic matrix. There is often a significant overlap between zones 3 and 4, which are sometimes referred to as a single zone of hypertrophy calcification.

5. The zone of ossification borders directly on the primary marrow cavity. It is characterized by intensely acidophilic osteoid, osteocytes within the bone matrix, and a monolayer of basophilic osteoblasts on the surface of the newly formed primary bone.

Secondary bone. In adults both dense and spongy bone are composed of secondary bone, or lamellar bone.

Secondary bone formation (remodeling)

Osteoclasts erode the primary bone matrix, blood and lymphatic vessels, nerves invade the cavity formed by the erosion, and osteogenic cells in the perivascular connective tissue are deposited on the walls of the cavity. Osteoblasts descended from these cells along with osteocytes released from their lacunae during resorption deposit the secondary bone in concentric layers, or lamellae, the oldest of which are farthest from the vessels. Owing to its greater organization, secondary bone is more efficient than the primary bone it replaces. Remodeling helps reshape growing bones to adapt to changing stresses and loads. It occurs continuously, even in adults, as secondary bone is eroded and replaced by new secondary bone. Secondary bone appears as a collection of densely packed bony cylinders, each with a central endosteum-lined Haversian canalcontaining lymphatic and blood vessels, nerves, and some loose connective tissue. The cylinder surrounding each canal is composed of a series of concentric lamellae. The collagen fibers in each lamella are oriented parallel to one another and nearly perpendicular to those in adjacent lamellae, an arrangement that lends added strength to the tissue. Osteocytes lie between the lamellae in rows of lacunae, their filopodia lie in canaliculi extending radially from each lacuna. Haversian canal, its contents, and the surrounding system of osteocytes and lamellae are termed a Haversian system, or osteon. Vascular connections between osteons are established by Volkmann’s canals, which run perpendicular to Haversian canals and cut across the lamellae. Osteons may bifurcate, but they he roughly parallel to one another and are held together by cementing substance, which fills the spaces between the cylinders. Often an old osteon is only partially eroded before a new one begins to form, so that wedge-shaped portions of old lamellae appear between recently formed osteons. The lamellae of partially eroded osteons are called interstitial lamellae.

Bone growth. Bones increase in size from birth into early adulthood. During this growth, the bone tissue is continuously remodeled. Growth occurs in 2 directions:

Growth in length of long bones is due primarily to the proliferation of chondrocytes in the resting cartilage and in the zone of proliferation of the epiphyseal plates, under the influence of growth hormone. Childhood levels of growth hormone cause cartilage to be produced in the epiphyseal plates as fast as it can be replaced by endochondral bone formation. At puberty, growth hormone levels decline and endochondral bone gradually overtakes and replaces the remaining cartilage, a process termed closure of the epiphyseal plates.

Growth in girth occurs by proliferation and differentiation of osteoprogenitor cells in the inner layer of the periosteum and deposition of new ossified tissue on the outer surface of the bone.

Bone repair. Bone fractures tear vessels in the periosteum, endosteum, and Haversian and Volkmann’s canals, causing local hemorrhage and clot formation between the broken ends of the bone. The periosteum and endosteum provide macrophages and fibroblasts, the former remove the clot, and the latter fill the breach with fibrous connective tissue. Some of the connective tissue cells differentiate into chondrocytes, and the connective tissue eventually becomes a calluscontaining islands of fibrocartilage and hyaline cartilage that serves as a model for bone formation. The presence of cartilage in the callus is typical of endochondral bones (eg, long bones), whereas flat membrane bones (eg, the mandible) typically heal without cartilage formation. Beginning in the subperiosteal region (as soon as 2 days after the injury in young people), the callus is gradually replaced by primary bone, which is subsequently remodelled and replaced by secondary bone. The time required for complete healing depends on the site and extents of the injury and is longer in older people.