Types of bone

The skeleton contains two types of bone. These are cortical (or compact) bone, which makes up most of shafts (diaphysis) of the long bones, such as the femur and tibia, and trabecular (also known as medullary) bone, which makes up most of the vertebral bodies and the ends of the long bones (Fig. 2.1).

FIGURE 2.1 Types of bone

Trabecular bone has a greater surface area than cortical bone and because of this it is remodelled more rapidly. This means that conditions associated with increased bone turnover tend to affect trabecular bone more quickly and more profoundly than cortical bone. Cortical bone is arranged in Haversian systems, which consist of a series of concentric lamellae of collagen fibres surrounding a central canal that contains blood vessels. Nutrients reach the central parts of the bone by an interconnecting system of canaliculi that run between osteocytes buried deep within bone matrix and lining cells on the bone surface. Trabecular bone has a similar structure, but here the lamellae run parallel to the bone surface, rather than concentrically as in cortical bone.

Bone composition

The organic component of bone matrix comprises mainly type I collagen, which is a fibrillar protein formed from three protein chains, wound together in a triple helix. Type I collagen is laid down by bone-forming cells (osteoblasts) in organized parallel sheets (lamellae) and, subsequently, the collagen chains become cross-linked by specialized covalent bonds, which help to give bone its tensile strength. When bone is formed rapidly (for example, in Paget’s disease, or in bone metastases), the lamellae are laid down in a disorderly fashion giving rise to ‘woven bone’, which is mechanically weak and easily fractured. Bone matrix also contains small amounts of other collagens and several non-collagenous proteins and glycoproteins. Some of these, such as osteocalcin, are specific to bone, whereas others, such as osteopontin, fibronectin and various peptide growth factors, are also found in other connective tissues. The function of non-collagenous bone proteins is unclear, but it is thought that they are involved in mediating the attachment of bone cells to bone matrix, and in regulating bone cell activity during the process of bone remodelling. The organic component of bone forms a framework upon which mineralization occurs. During bone formation, osteoblasts lay down uncalcified bone matrix (osteoid), which contains the components described above, and small amounts of other proteins, which are adsorbed from extracellular fluid. After a lag phase of about 10 days, the matrix becomes mineralized, as hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂] crystals are deposited in the spaces between collagen fibrils. Mineralization confers upon bone the property of mechanical rigidity, which complements the tensile strength and elasticity derived from bone collagen.

Bone formation, modelling and remodelling

Bone is formed through the process of osteogenesis early during embryonic life and is modelled thereafter as the skeleton grows until early adulthood, when peak bone mass is attained. Thereafter, bone constantly undergoes remodelling. The function of remodelling is to repair and renew damaged bone, but in later life the net amount of bone removed during remodelling exceeds that which is replaced, resulting in bone loss. In old age, subtle changes in bone shape occur with remodelling, particularly in the long bones, leading to a slight increase in cross-sectional area (cortical expansion) with cortical thinning.

Bone remodelling

The mechanical integrity of the skeleton is maintained by the process of bone remodelling, which occurs throughout life, in order that damaged bone can be replaced by new bone (Fig. 2.2). Remodelling of the bone occurs in response to alterations in type or amount of mechanical stresses (or to the lack of them). Remodelling can be divided into four phases: resorption, reversal, formation and quiescence. At any one time approximately 10% of bone surface in the adult skeleton is undergoing active remodelling, whereas the remaining 90% is quiescent.

FIGURE 2.2 Bone remodelling cycle

Osteoclast formation and differentiation

Remodelling commences with attraction of bone-resorbing cells (osteoclasts) to the site that is to be resorbed. These are multinucleated phagocytic cells, rich in the enzyme tartrate-resistant acid phosphatase, and are formed by fusion of precursors derived from the cells of monocyte/macrophage lineage. Osteoclast formation and activation is dependent on close contact between osteoclast precursors and bone marrow stromal cells. Stromal cells secrete the cytokine M-CSF (macrophage colony-stimulating factor), which is essential for differentiation of both osteoclasts and macrophages from a common precursor. Stromal cells also express a molecule called RANK ligand (RANKL) on the cell surface, which interacts with another cell surface receptor present on osteoclast precursors called RANK (receptor activator of nuclear factor kappa B) to promote differentiation of osteoclast precursors into mature osteoclasts. The RANK–RANKL interaction is blocked by another molecule called osteoprotegerin (OPG), which is a ‘decoy’ ligand for RANK and a potent inhibitor of osteoclast formation.

Mature osteoclasts form a tight seal over the bone surface and resorb bone by secreting hydrochloric acid and proteolytic enzymes through the ‘ruffled border’ into a space beneath the osteoclast (Howship’s lacuna). The hydrochloric acid secreted by osteoclasts dissolves hydroxyapatite and allows proteolytic enzymes (mainly cathepsin K and matrix metalloproteinases) to degrade collagen and other matrix proteins (Fig. 2.3). Molecules that have been identified as being important in regulating osteoclast activity include carbonic anhydrase II (CA-II), which catalyses the formation of hydrogen ions within osteoclasts; TCIRG1, which encodes a subunit of the osteoclast proton pump, necessary to pump hydrogen ions into the space beneath the osteoclasts; CLCN7, which encodes a chloride channel necessary for transport of chloride ions into the space under the osteoclast; and cathepsin K, which degrades collagen and other non-collagenous proteins. Mutations in the genes that encode these proteins lead to osteopetrosis, which is a disease associated with increased bone density and osteoclast dysfunction. After resorption is completed, osteoclasts undergo programmed cell death (apoptosis), in the so-called reversal phase, which heralds the start of bone formation. It has recently been discovered that many of the drugs that are used clinically to inhibit bone resorption, such as bisphosphonates and oestrogen, do so by promoting osteoclast apoptosis.

FIGURE 2.3 Regulation of osteoclast differentiation

Osteoblast formation and differentiation

Bone formation begins with the attraction of osteoblast precursors, which are derived from mesenchymal stem cells in the bone marrow, to the bone surface. Although these cells have the potential to differentiate into many cell types, including adipocytes, myocytes and chondrocytes, it is now known that the key trigger for osteoblast differentiation is expression of a regulatory molecule called CBFA1 (core binding factor alpha1) in pre-osteoblasts. CBFA1 is a transcription factor that activates coordinated expression of genes characteristic of the osteoblast phenotype, such as osteocalcin, type I collagen and alkaline phosphatase. Recent studies have identified another molecule called ‘osterix’ that is equally important for the regulation of bone formation. Like CBFA1, osterix is a transcription factor and is necessary for differentiation of mesenchymal cells into osteoblasts. The disease cleido-cranial dysplasia (absence of clavicles and cranial defects) is caused by haplo-insufficiency of CBFA1 (complete deficiency is lethal). Haplo-insufficiency means that the protein produced by a single copy of an otherwise normal gene is not sufficient for normal function. Bone formation is stimulated by Wnt proteins which bind to and activate lipoprotein receptor-related protein 5 (LRP5), which is expressed on osteoblasts and osteoblast precursors. This process is inhibited by other molecules, most notably Sclerostin (SOST) which is produced by osteocytes and binds to LRP5 preventing its activation by Wnt.

Mature osteoblasts are plump cuboidal cells that are responsible for the production of bone matrix. They are rich in the enzyme alkaline phosphatase and the protein osteocalcin, and circulating levels of these are used clinically as markers of osteoblast activity. Osteoblasts lay down bone matrix, which is initially unmineralized (osteoid) but which subsequently becomes calcified after about 10 days to form mature bone. During bone formation, some osteoblasts become trapped within the matrix and differentiate into osteocytes, whereas others differentiate into flattened ‘lining cells’, which cover the bone surface. Osteocytes connect with one another and with lining cells on the bone surface by an intricate network of cytoplasmic processes, running through canaliculi in bone matrix. Osteocytes are thought to act as sensors of mechanical strain. In response to mechanical loading, release of SOST by osteocytes decreases, stimulating bone formation. Osteocytes are also the main source of fibroblast growth factor 23 (FGF23), which is a circulating hormone that regulates phosphate excretion.

Regulation of bone remodelling

Bone remodelling is a highly organized process, but the mechanisms that determine where and when remodelling occurs are poorly understood. Mechanical stimuli and areas of micro-damage are likely to be important in determining the sites at which remodelling occurs in the normal skeleton. Increased bone remodelling may result from local or systemic release of inflammatory cytokines such as interleukin-1 and tumour necrosis factor (TNF) in inflammatory diseases. Calciotropic hormones, such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D, act together to increase bone remodelling, which allows skeletal calcium to be mobilized for maintenance of plasma calcium homeostasis. Bone remodelling is also increased by other hormones, such as thyroid hormone and growth hormone, but suppressed by oestrogen, androgens and calcitonin (Table 2.1).

Table 2.1 Stimulators and inhibitors of bone remodelling

^aSex hormones stimulate bone turnover during skeletal growth, but inhibit turnover during adulthood.

^bThese factors mainly affect bone resorption.

^cThese factors mainly affect bone formation.