Bone Modeling and Remodeling

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Chapter 15 Bone Modeling and Remodeling

The structure and composition of bone provide it with excellent failure resistance while retaining relatively low mass. These are close to ideal properties for its function within the musculoskeletal system. Even though frequently perceived as an inert material, bone is an extremely live tissue with extensive remodeling activity in response to injuries or simple wear due to everyday stresses. Its high metabolic activity plays a fundamental role in the body’s mineral homeostasis, and yet it gives bone a unique characteristic among tissues: the ability to heal without scar formation.

This chapter discusses bone structure, cells, and extracellular matrix, the mechanical and chemical stimulants and inhibitors of bone activity, and the interaction among these components that leads to bone formation and remodeling both in physiologic situations and in response to injury.

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.¹ 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.¹^–³

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,¹ whereas the vertebral bodies have a thin shell of compact trabecular bone with no true cortical structure.³

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).^3,⁴ 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 appositional³^–⁶

Immature bone is woven.^1,^3,^4,^7,⁸ 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.^1,^3,⁴

Mature bone is lamellar.^1,^3,^4,^7,⁸ Lamellar bone is stress oriented, stronger, and less flexible, and has slower turnover compared with woven bone.^1,^3,⁴ There are two different types of lamellar bone: cortical (compact) and cancellous (spongy or trabecular).^1,^3,^4,⁸^–¹² 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.^9,¹³ 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.^8,¹⁴^–¹⁶

Cortical bone, composed of tightly packed osteons, makes up 80% of the skeleton.^1,^4,¹⁰ Trabecular bone has a surface area per unit volume 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.^9,¹⁷

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.¹⁸^–²⁰ Several studies have also shown that new bone is formed in response to tumors and infections.²¹^–²⁴ It has been shown that osteoblasts have the ability to form bone during distraction osteogenesis,²⁵^–³¹ 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 and fusion (ACDF) and plating, a 97.5% rate of fusion with new bone formation has been achieved with either autograft or allograft.³² In a recent study, Jensen et al. showed an 86% union rate after single- and multiple-level ACDF using patellar allograft and plating.³³ In a study from Japan, Momma et al. reported complete bone remodeling on CT scan 6 to 12 months after the use of β-tricalcium phosphate to fill a partial vertebrectomy defect created for cervical decompression surgery.³⁴

Vertebral Bone Formation

Because the vertebrae are short bones, they ossify through endochondral ossification.³^–⁵ The process begins with the concentration of undifferentiated cells that transform into chondrocytes and secrete a hyaline or hyaline-like cartilaginous matrix.^5,^6,^10,^35,³⁶ The chondrocytes enlarge and vascular buds invade the cartilage, bringing other progenitor cells that differentiate into osteoblasts that in turn start forming bone on the cartilaginous frame. Osteoclasts then reabsorb the ossified cartilage and immature bone. Osteoblasts finally fill this space with mature lamellar bone.³^–⁵

Ossification Centers of the Vertebrae

By the sixth gestational week, centers of cartilage formation (chondrification) develop in each vertebra. Two chondrification centers develop in each half of the central vertebral body. A hemivertebra occurs when these centers fail to form in one side of the vertebral body. Centers of cartilage formation also develop in each half of the vertebral arches. Next, cartilaginous transverse and spinous processes develop from the primitive arches.³⁷ It has been shown that bone morphogenetic protein 4 is required for the development of the cartilaginous spinous process.³⁸

The primary ossification centers develop in utero. In the vertebra, three primary centers form around the eighth week of gestation. One is located in the center of the body and one in each vertebral arch. Bone forms on the pre-existing vertebral cartilage template.³^–⁵ ³⁷ Primary ossification begins in the lower thoracic spine, then progresses in the cranial and caudal directions.³⁹ The five secondary centers of ossification develop after birth: one at the tip of the spinous process, one at the tip of each transverse process, and one anular center at the ventral portion of the superior and inferior end plates. They start to ossify at approximately 15 to 16 years of age and fuse with the remaining osseous vertebra by the middle of the third decade of life.^37,⁴⁰

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.⁴¹ 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 end results of the activity of a vast array of cells that work in harmony to create bone while maintaining the body’s mineral homeostasis.³^–⁵ ¹⁰

Bone Modeling during Growth

During growth, coordinated osteal resorption and formation change the size and shape of bone.¹⁷ The physes grow and make the bone longer and narrower. The metaphysis also changes its shape, becoming narrower to match the rest of the bone. Appositional periosteal ossification increases the diaphysial diameter.⁵ At the same time, the cortices becomes thinner and the medullary canal larger owing to intensified bone resorption on the endosteal side.^42,⁴³

Physiologic Bone Remodeling after Growth

Throughout life, in situ removal and replacement of bone take place without changing bone form or density. Remodeling occurs on both the surface and the interior of the bone (internal remodeling). Both processes basically start with osteoclast activation. Internal remodeling commences with osteoclasts reabsorbing bone by cutting conical spaces through old osteonal systems.³^–⁵ ^,17 ^,44 Spindle cells, osteoblasts, and blood vessels fill the conical spaces cut by the osteoclasts. Osteoblasts deposit successive lamellae of new osteoid matrix, which will later mineralize. It takes about 50 osteoblasts to fill the cone cut by 1 osteoclast. Internal remodeling is seen in cortical bone.

Surface remodeling occurs on trabecular (which comprises most of the vertebral body), endosteal, and periosteal bone and is very similar to internal remodeling, except that instead of cutting cones, osteoclasts run on the surface of the lamellae excavating a cavity, the so-called Howship lacuna. The rest of the process resembles internal remodeling. Physiologic remodeling serves to repair damaged bone matrix as well as to maintain mineral homeostasis.³^–⁵

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.^44,⁴⁵

Osteoclasts are derived from hematopoietic stem cells. They exit the circulation close to the site to be remodeled.⁴⁵ 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.^46,⁴⁷ 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,^48,⁴⁹ microphthalmia-associated transcription factor (MITF),^50,⁵¹ and nuclear factor of activated T cells, calcineurin dependent-1 (NFAT-c1).^51,⁵²

The receptor on the osteoclast for RANKL is called RANK.⁵³ Concomitantly, another factor, also produced by stromal cells and osteoblasts, was found that inhibits the activity of RANKL; it was named osteoprotegerin (OPG).⁵⁴ 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.⁵⁵^–⁵⁷ 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.⁵⁸ The only exception to this is the hormone calcitonin, which does not use the RANKL/OPG axis, instead acting directly on the osteoclast receptors.^3,⁴ The mature osteoclast then engages in bone resorption by peripheral attachment to the bone matrix using the β3 integrin,⁵⁹ 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 matrix⁶⁰ (Fig. 15-1).

FIGURE 15-1 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 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.³^–⁵ ⁴⁵ Expression of the transcription factors runt-related transcription factor-2 (Runx2), distal-less homeobox-5 (Dlx5), msh homeobox homologue-2 (Msx2),⁶¹^–⁶⁵ and osterix (Osx), as well as activation of several components of the Wnt signaling pathway,^62,⁶⁶^–⁶⁹ are required for osteoblastic differentiation (Fig. 15-2).

FIGURE 15-2 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.⁷⁰ 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 cell⁴⁵ (Fig. 15-3).

FIGURE 15-3 Osteocyte morphology. Left, Scanning electron micrograph of isolated osteocytes in culture. After attachment, osteocytes form cytoplasmic extrusions in all directions. Right, Scanning electron micrograph of osteocytes embedded in calcified bone matrix. 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.)

Age-Related Bone Remodeling (Bone Loss)

Bone density changes drastically with age.³^–⁵ ^,41 ^,45 ^,71 Peak bone mass is reached approximately 10 years after cessation of skeletal growth. Subsequently, bone mass begins to decline and reaches approximately 50% of its peak value by the eighth or ninth decade of life.⁵ Men lose an average of 30% less bone mass than women in a lifetime. In women, extensive loss of bone density starts immediately after menopause and lasts for about 10 years. It is believed to be closely related to the decline in estrogen levels.^41,⁷²^–⁷⁴ Trabeculae decrease more in number than in thickness and the rate of endosteal resorption begins to exceed the amount of periosteal apposition. The bone, with fewer trabeculae and thinner cortices, becomes more fragile. Interestingly, Jaworski and Uhthoff have demonstrated that loss of bone mass due to disuse is caused by increased endosteal resorption in older dogs but mainly by slowing of periosteal apposition in younger dogs with growing skeletons.^75,⁷⁶