Types of Bone

Based on general shape, bones can be classified into three groups: short, flat, and long or tubular. The femur, tibia, and phalanges are examples of long bones. Tubular or long bones have an expanded metaphysis and an epiphysis at either end of a thick cortical wall diaphysis. The shaft (diaphysis) is responsible for withstanding primarily torsional and bending stresses, whereas the metaphyseal portion, with its greater deformation under the same load, has become specialized in absorbing impact to protect the articular cartilage.

Short bones, such as the vertebral bodies and tarsal and carpal bones, measure approximately the same length in all dimensions and are roughly cuboid in shape, with slight variations. They are all mainly composed of loose trabecular bone, like the metaphysis of the long bones. The main function of this bone aggregate is, again, absorbing the body’s weight. The carpals and tarsals have very thin cortices, whereas the vertebral bodies have a thin shell of compact trabecular bone with no true cortical structure.

The iliac crests, the skull vault, and the vertebral laminae are examples of flat bones.

Long and short bones ossify using a previously formed cartilage model (endochondral ossification), whereas flat bones form from the condensation and mineralization of loose mesenchymal tissue (intramembranous ossification). A third type of ossification that occurs when osteoblasts line the periosteum of an existing bone surface and start secreting osteoid in layers, hence making the bone thicker, is termed appositional.

Immature bone is woven. It is found in the embryonic skeleton, fracture callus, and bone neoplasms. It is less organized, weaker, and more flexible, and has increased turnover compared with mature bone. Woven bone does not have the ability to remodel following the stress pattern.

Mature bone is lamellar. Lamellar bone is stress oriented, stronger, less flexible, and has slower turnover compared with woven bone. There are two different types of lamellar bone: cortical (compact) and cancellous (spongy or trabecular). Even though cortical and cancellous bone have the same structure and composition, their mechanical properties are very different because of their differences in density and distribution. Cancellous bone is 50% to 90% porous, whereas cortical bone has a porosity of approximately 10%. This difference in density makes cortical bone 10 times stronger in compression than the trabecular variant.

Cortical bone, composed of tightly packed osteons, makes up 80% of the skeleton. Trabecular bone has a surface area per unit volume that is approximately 20 times that of cortical bone. Almost all of its cells lie between lamellae or on the surface of trabeculae, in close contact with the bone marrow, which makes them much more metabolically active than the cortical bone cells surrounded by bone matrix.

Bone Formation

The formation and maintenance of the skeleton require that bone be produced constantly. Osteoblasts fabricate bone in response to many stimuli and under different conditions, including growth, physiologic remodeling, fracture healing, and heterotopic ossification. Several studies have also shown that new bone is formed in response to tumors and infections. It has been shown that osteoblasts have the ability to form bone during distraction osteogenesis, depositing new bone in the void initially filled by autologous or allogenic bone graft, demineralized bone matrix, or synthetic bone substitutes. In anterior cervical discectomy fusion (ACDF) and plating, a 97.5% rate of fusion with new bone formation has been achieved with either autograft or allograft. A study by Jensen and colleagues showed an 86% union rate after single- and multiple-level ACDF using patellar allograft and plating. In a study from Japan, Momma and colleagues reported complete bone remodeling on computed tomography (CT) scan 6 to 12 months after the use of β-tricalcium phosphate to fill a partial vertebrectomy defect created for cervical decompression surgery.

Bone Modeling and Remodeling

In general, modeling alludes to bone turnover that alters the shape of the bone, whereas remodeling is the turnover that recycles bone without changing its shape. Bone turnover approaches 100% during the first year of life. Most of the bone turnover during skeletal growth derives from modeling. After the completion of skeletal growth, bone turnover results primarily from remodeling. Bone modeling and remodeling are the results of the activity of a vast array of cells that work in harmony to create bone while maintaining the body’s mineral homeostasis.

Bone Modeling and Remodeling and the Basic Multicellular Unit

Bone modeling and remodeling are performed by the basic multicellular unit (BMU), a temporary anatomic structure comprising osteoclasts and osteoblasts that replace older packets of bone with new bone tissue.

Osteoclasts are derived from hematopoietic stem cells. They exit the circulation close to the site to be remodeled. The mononuclear hematopoietic cell’s fusion into a polykaryon (immature osteoclast) requires the presence of macrophage colony-stimulating factor (M-CSF), a growth factor, and the receptor activator of nuclear factor κB ligand (RANKL), a tumor necrosis factor produced by osteoblasts. Further differentiation of the immature osteoclast occurs under the influence of RANKL and many other genes, including the activator protein-1 (AP-1) family member c- fos , microphthalmia-associated transcription factor (MITF), and nuclear factor of activated T cells, calcineurin dependent-1 (NFAT-c1).

The receptor on the osteoclast for RANKL is called RANK. Concomitantly, another factor, also produced by stromal cells and osteoblasts, was found that inhibits the activity of RANKL; it was named osteoprotegerin (OPG). OPG is a soluble decoy receptor for RANKL, and its function is to reduce osteoclastogenesis by competitively occupying the stromal RANKL binding sites on osteoclast RANK receptors. The RANKL/OPG signaling axis provides a mechanism through which stromal cells control osteoblastic activity. Factors that exhibit a strong effect on resorption (e.g., parathyroid hormone, prostaglandins, interleukins, vitamin D, and corticosteroids) all signal to the osteoblast/stromal cell, which then appears to translate the message to the osteoclast through the RANKL/OPG axis. The only exception is the hormone calcitonin, which does not use the RANKL/OPG axis, instead acting directly on the osteoclast receptors. The mature osteoclast then engages in bone resorption by peripheral attachment to the bone matrix using the β3 integrin, which creates a microcompartment between the osteoclast’s ruffled basal border and the bone surface. Hydrogen ions are pumped into the compartment by the osteoclast to digest the mineral component. Next, protease is released to degrade the organic matrix ( Fig. 27-1 ).

Osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and RANK ligand (RANKL) are produced selectively by numerous cell types and a variety of tissues, such as lymphocytes, osteoblasts, and endothelial cells. There are three main biologic systems where this molecular triad is particularly important: the osteoarticular, immune, and vascular systems. RANKL is not only a dendritic cell survival factor, but it strongly induces osteoclastogenesis and then bone resorption through its binding to RANK. OPG inhibits osteolysis and blocks RANKL-RANK interaction. Although the OPG/RANK/RANKL triad is the main modulator of bone apposition-resorption coupling, other controls of osteoclastic differentiation also exist, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), which can modulate the biologic activities of the triad. OPG/RANKL/RANK should be considered as an osteoimmunomodulator complex.

(From Theoleyre S, Wittrant Y, Kwan Tat S, et al: The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 15:457–475, 2004.)

Osteoblasts are derived from mesenchymal stem cells from the bone marrow and periosteum. Expression of the transcription factors runt-related transcription factor-2 (Runx2), distal-less homeobox-5 (Dlx5), msh homeobox homologue-2 (Msx2), and osterix (Osx), as well as activation of several components of the Wnt signaling pathway are required for osteoblastic differentiation ( Fig. 27-2 ).

Schematic representation of the role of Wnt signaling in osteoblast differentiation and function and, indirectly, in osteoclast differentiation and activation. OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor κB ligand.

(From Baron R, Rawadi G, Roman-Roman S: Wnt signaling: a key regulator of bone mass. Curr Top Dev Biol 76:103–127, 2006.)

The mature osteoblast produces proteins like type I collagen, osteocalcin, and alkaline phosphatase, the latter a key enzyme in bone mineralization. Osteoblasts become entrapped in their own osteoid matrix and extrude long cytoplasmic processes to remain in contact with surrounding cells. They then start expressing a whole new set of genes to continue bone turnover and maintain mineral homeostasis. These cells are now considered osteocytes, the mature bone cell ( Fig. 27-3 ).

Osteocyte morphology. Scanning electron micrograph of isolated osteocytes in culture (left). After attachment, osteocytes form cytoplasmic extrusions in all directions. Scanning electron micrograph of osteocytes embedded in calcified bone matrix (right). Note the many cell processes radiating from the osteocyte cell bodies. Magnification ×1000.

(From Klein-Nulend J, Bacabac RG, Mullender MG: Mechanobiology of bone tissue. Pathol Biol [Paris] 53:576–580, 2005.)

Modeling and Remodeling in Response to Mechanical Forces

For many years, the effect of mechanical forces on bone remodeling has intrigued investigators. In the 17th century, Galileo had already noted the correlation of bone size and body weight and activity. In the 19th century, Wolff made the landmark observation that bone structure and remodeling have a clear relationship with loading and that this association can be expressed mathematically. The adaptive changes of bone in response to loading are therefore frequently referred to as following Wolff’s law. Several studies have shown that bone adapts to loading and that maintenance of adequate bone density requires cyclic loading. Goodship and colleagues have experimentally proved with animal studies that after resection of the ulna, the radius increases in size and compensates or nearly compensates for the loss. Excessive repetitive loading and vigorous exercise are also known to stimulate bone formation. Increased shaft circumference and bone density have been noted on the dominant humerus of tennis players. Although not precisely quantified, the absence of loading has a negative effect on bone mass. Uhthoff and coworkers have reported on loss of bone mass after immobilization/bed rest due to skeletal traction, and adjacent to rigid implants.

Regaining bone mass after prolonged disuse may take several months, even in children. In some individuals, especially the elderly, it may never return to its previous level. Disuse results in suppressed periosteal apposition in growing bone and enhanced endocortical resorption in mature bone.

Mechanotransduction

It is currently believed that the mechanical adaptation of bone is governed by the osteocytes, which respond to a loading-induced flow of interstitial fluid through the lacuno-canalicular network by producing signaling molecules ( Fig. 27-4 ).

Model for the transduction of mechanical strain to osteocytes in bone. The diagram at left depicts the network of osteocytes and lining cells of a piece of bone tissue under stress (vertical arrows) . Loading results in flow of interstitial fluid in the canalicular nonmineralized matrix (horizontal arrow) .

(From Klein-Nulend J, Bacabac RG, Mullender MG: Mechanobiology of bone tissue. Pathol Biol [Paris] 53:576–580, 2005.)

It has been shown that mechanical load induces fluid flow in the canalicular network. Weinbaum and colleagues suggested that this fluid flow is a physical mediator of mechanosensing by osteocytes in vivo. The osteocytes respond to mechanical stimuli with the production of signaling molecules that modulate the activities of osteoblasts and osteoclasts, thus converting mechanical stimuli into cellular signals that affect bone modeling and remodeling.

Loading results in adaptive changes in bone, making it stronger. This adaptive response is regulated by the ability of resident bone cells to perceive and translate mechanical energy into a cascade of structural and biochemical changes within the cells, a process known as mechanotransduction.

Osteocytes probably do not respond directly to mechanical strain (deformation) of bone tissue, but respond indirectly to extracellular fluid flow caused by loading. When osteocytes and osteoblasts are subjected to these changes in fluid pressure, they release several bone-forming growth factors, including nitric oxide and prostaglandins. Certain prostaglandins, particularly PGE2, are anabolic with a demonstrated capacity to stimulate osteoblast activity and new bone formation. Nitric oxide, a strong inhibitor of bone resorption, works in part by suppressing the expression of RANKL and increasing the expression of OPG.

Fluid flow along cell bodies produces drag force, fluid shear stress, and an electric potential. Each of these signals might activate bone cells, although cell culture experiments by Hung and colleagues and Reich and colleagues suggest that cells are less sensitive to electrical potentials than they are to fluid forces.

There are several hormones that might amplify or transduce the effects of mechanical loading, including parathyroid hormone, estrogen, and insulin-like growth factors. Sawakami and associates have suggested that an important event linking mechanical loading to bone formation is Wnt signaling through the LRP5 receptor pathway.

Genetic Factors

Bone modeling and remodeling can be deeply affected by genetic imprint. Diseases like osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and pycnodysostosis result from well-established genetic abnormalities. The same holds true for some types and grades of osteoporosis.

Systemic Hormones

The hormones that most directly affect bone turnover and mineral hemostasis are parathyroid hormone (PTH) and calcitonin. Vitamin D also plays an important role. Modeling and remodeling of bone and mineral hemostasis are secondarily influenced by thyroxine (thyroid hormone), glucocorticoids, and estrogen.

PTH is a single-chain polypeptide secreted by the chief cells of the parathyroid gland. It increases extracellular calcium levels by raising the renal tubular reabsorption of calcium and also by intensifying calcium release from bone due to increased bone resorption. PTH also stimulates the production of 1,25-dihydroxyvitamin D, which increases renal and gastrointestinal absorption of calcium, as well as its release from bone.

Calcitonin is a polypeptide synthesized by the C cells of the thyroid gland. It lowers serum calcium levels by inhibiting osteoclastic bone resorption. Contrary to PTH, which acts on the osteoblasts to activate osteoclasts, calcitonin has a direct effect on osteoclast inhibition.

The active form of vitamin D (1,25-dihydroxyvitamin D) is formed in the kidneys. Although its primary function is to increase the blood level of calcium by increasing calcium absorption in the gut and kidneys, it is also a powerful stimulator of bone resorption by osteoclasts.

Thyroid hormone can stimulate resorption of bone by osteoclasts that can lead to loss of bone mass. Studies suggest that the bone loss seen in hyperthyroidism may be caused by the catabolic action of the elevated thyroid hormone itself or by the decreased anabolic action of thyroid-stimulating hormone.

Glucocorticoids decrease bone mass not only by decreasing osteoid formation through osteoblast inhibition; they increase bone resorption by stimulating osteoclast activity. Studies have found that glucocorticoids cause an early and profound reduction in formation of bone through direct inhibition of osteoblasts. Glucocorticoids also increase bone resorption by stimulating production of OPG-L and inhibiting the production of OPG by osteoblasts, hence stimulating bone resorption by osteoclasts. Glucocorticoids have also been shown to stimulate the apoptosis of osteoblasts.

Finally, estrogens exert a series of complex effects on bone, either directly by inhibiting bone resorption and total turnover or indirectly by acting on calcitonin, vitamin D, or parathyroid hormone. One study suggests that estrogen partially controls osteoblast and osteoclast function, is possibly involved in regulating mechanotransduction, and also interacts with the Wnt/β-catenin pathway.

Exercise

Various authors have demonstrated that repetitive bone loading increases bone mass and decreased loading reduces it. Brighton and coworkers demonstrated that cyclical strain can stimulate bone cell function in culture. It is currently accepted that loading results in adaptive changes in bone, making it stronger. Bone’s adaptive response is regulated by the ability of resident bone cells to perceive and translate mechanical energy into a cascade of structural and biochemical changes within the cells, a process known as mechanotransduction.

Strain is defined as the deformation or change in dimension or shape caused by a load in any structure or structural material. Strain is expressed in microstrain units (millionths of a 100% strain), where 1000 microstrain units in compression would shorten a bone by 0.1% of its length. The amount of strain suffered by the bone during load application also influences the organization and density of newly formed bone. Minimal strain will cause the formation of a dense, well-organized bone. Moderate strain will result in the formation of less dense, woven bone. A large amount of strain will lead to the formation of fibrous tissue. All of these strain effects are probably mediated through the mechanotransduction pathway.