There are two types of bone: (a) compact or cortical bone and (b) trabecular or cancellous bone. Cortical bone is found principally in the shafts (diaphyses) of long bones. It consists of a number of irregularly spaced overlapping cylindrical units termed Haversian systems. Each consists of a central Haversian canal surrounded by concentric lamellae of bony tissue (Fig. 5.2A). Trabecular bone is found principally at the ends of long bones, and in vertebral bodies and flat bones. It is composed of a meshwork of trabeculae within which are intercommunicating spaces (Fig. 5.2B).

The skeleton consists of approximately 80% cortical bone, largely in peripheral bones, and 20% trabecular bone, mainly in the axial skeleton. These amounts vary according to site and relate to the need for mechanical support. While trabecular bone accounts for the minority of total skeletal tissue, it is the site of greater bone turn-over because of its different structure and because its total surface area is greater than that of cortical bone.

Bones are generally richly supplied with blood, via periosteal vessels, vessels that enter close to the articular surfaces and nutrient arteries passing obliquely through the cortex before dividing into longitudinally directed branches. Loss of the arterial supply to parts of a bone can result in death of bone tissue, usually called avascular necrosis or osteonecrosis. Certain bones in the body are prone to this complication, usually after injury, including the head of the femur (discussed later in this chapter), the scaphoid bone in the wrist, the navicular in the foot and the tibial plateau. Nutrient arteries to the scaphoid bone are large and numerous at the distal end but become sparse and finer as the proximal pole is approached. Fractures of the scaphoid, especially of the waist or proximal pole, may be associated with inadequate blood supply resulting in necrosis and later secondary osteoarthritis in the wrist. In the foot, the navicular bone is the last tarsal bone to ossify and its ossification centre may be dependent on a single nutrient artery. Compressive forces on weight bearing are thought to be the cause of avascular necrosis of the ossification centre, which usually presents as a painful limp in a child. This condition is also known as Kohler’s disease.

In addition to its role as a support structure, the bone’s other primary function is calcium homeostasis. More than 99.9% of the total body calcium resides in the skeleton. The maintenance of normal serum calcium depends on the interplay of intestinal calcium absorption, renal excretion and skeletal mobilization or uptake of calcium. Serum calcium represents less than 1% of total body calcium but the serum level is extremely important for maintenance of normal cellular functions. Serum calcium regulates and is regulated by three major hormones: parathyroid hormone (PTH), 1,25-dihydroxyvitamin D and calcitonin (Fig. 5.3). Parathyroid hormone is an 84-amino acid peptide secreted by the four parathyroid glands located adjacent to the thyroid gland in the neck. Calcitonin is a 32-amino acid peptide secreted by the parafollicular cells of the thyroid gland. Vitamin D, from dietary sources (D₃) or synthesized in skin (D₂), is converted to 25-hydroxyvitamin D in the liver and then to 1,25-dihydroxyvitamin D in the kidney.

PTH and 1,25-dihydroxyvitamin D are the major regulators of calcium and bone homeostasis. Although calcitonin can directly inhibit osteoclastic bone resorption, it appears to play a relatively minor role in calcium homeostasis in normal adults. PTH acts on the kidney to increase calcium reabsorption, phosphate excretion and 1,25-dihydroxyvitamin D production. It acts on bone to increase bone resorption. 1,25-dihydroxyvitamin D is a potent stimulator of bone resorption and an even more potent stimulator of intestinal calcium (and phosphate) absorption. It is also necessary for bone mineralization. Intestinal calcium absorption is probably the most important calcium homeostatic pathway.

A number of feedback loops operate to control the level of serum calcium and the two major calcium homeostatic hormones. A calcium-sensing receptor, identified in para-thyroid and kidney cells but also found in other tissues, which senses extracellular calcium levels plays a critical role in calcium homeostasis. Low serum calcium levels stimulate 1,25-dihydroxyvitamin D synthesis directly through stimulation of PTH release (and synthesis). The physiological response to increasing levels of PTH and 1,25-dihydroxyvitamin D is a gradual rise in serum calcium level. To prevent an elevated level of serum calcium, a second set of feedback loops operate to decrease PTH and 1,25-dihydroxyvitamin D levels. These feedback loops maintain serum calcium within a narrow physiological range. Disturbances in these control mechanisms or over/underproduction of these three major hormones can lead to various clinical states, discussed in more detail below. A PTH-related peptide (PTHrP) also plays a role in calcium homeostasis, especially in the fetus and in the growing skeleton.

The structural components of bone consist of extracellular matrix (largely mineralized), collagen and cells. The collagen fibres are of type I, comprise 90% of the total protein in bone and are oriented in a preferential direction giving lamellar bone its structure. Spindle- or plate-shaped crystals of hydroxyapatite [3Ca₃(PO₄)₂]·(OH)₂ are found on the collagen fibres, within them, and in the ground substance. The ground substance is primarily composed of glycoproteins and proteoglycans. These highly anionic complexes have a high ion-binding capacity and are thought to play an important role inthe calcification process. Numerous non-collagenous proteins have been identified in bone matrix, such as osteocalcin synthesized by the osteoblasts, but their role is unclear.

The principal cells in bone are the osteoclasts, osteo-blasts and osteocytes. Osteoclasts, the cells responsible for resorption of bone, are derived from haematopoietic stem cells. Osteoblasts are derived from local mesenchymal cells. They are responsible directly for bone formation and indirectly, via paracrine factors, for regulating osteoclastic bone resorption. Osteocytes are formed when osteoblasts become entombed within the hard mineralized matrix. More than 90% of all cells within the adult skeleton are osteocytes. Osteocytes are thought to sense mechanical loads on the skeleton and have a dendritic structure that allows communications with other cells via gap junctions so that bone fluid flow shear stress can be translated into biochemical signals that direct bone modeling and remodelling.

Various cytokines control osteoclast recruitment and activity, including interleukin-1β (IL-1β) and IL-6. A transmembrane protein belonging to the tumour necrosis factor superfamily, plays an important role in osteoclast differentiation and activity (Fig. 5.4A). Its receptor is called RANK (receptor activator of NFкB) since, after binding, a transcriptional factor known as NFкB translocates to the nucleus and appears responsible for expression of genes that lead to the osteoclast phenotype. This process is inhibited by a soluble receptor, osteoprotegerin (OPG), which competes for binding of RANK ligand to produce an inactive complex. Control of osteoblast differentiation and function is achieved by integration of a number of pathways. Bone morphogenetic proteinsand the Wnt signalling pathway are important modulators of osteoblast function and hence bone formation. Sclerostin, a product of the osteocyte, antagonizes the Wnt signalling pathway, which can inhibit osteoblast generation.

Bone is continually undergoing renewal called remodelling (Fig. 5.4B). In the normal adult skeleton, new bone laid down by osteoblasts exactly matches osteoclastic bone resorption, i.e. formation and resorption are closely ‘coupled’. Although there is a lesser amount of trabecular bone than cortical bone in the skeleton, because trabecular bone ‘turns over’ between 3–10 times more rapidly than cortical bone, it is more sensitive to changes in bone resorption and formation. Most bone turnover occurs on bone surfaces, especially at endosteal surfaces. Moreover, the rate of remodelling differs in different locations according to physical loading, proximity to a synovial joint or the presence of haematopoietic rather than fatty tissue in adjacent marrow.

Bone remodelling follows an ordered sequence, referred to as the basic multicellular unit of bone turnover or bone remodelling unit (BMU). In this cycle, bone resorption is initiated by the recruitment of osteoclasts, which act on matrix exposed by proteinases derived from bone lining cells. In cortical bone, a resorptive pit (called a Howship’s lacuna) is created by the osteoclasts. Osteoclasts have a convoluted membrane called a ruffled border through which lysosomal enzymes are released into pockets, causing matrix resorption. This resorptive phase is then followed by a bone formation phase where osteoblasts fill the lacuna with osteoid. The latter is subsequently mineralized to form new bone matrix. This cycle of coupling of bone formation and resorption is vital to the maintenance of the integrity of the skeleton. Uncoupling of the remodelling cycle, so that bone resorption or formation are in excess of each other leads to net bone change (gain or loss).

In clinical practice, it is possible to measure serum biochemical markers of bone remodelling that reflect bone formation and bone resorption (Table 5.1). These markers have been shown to be independent predictors of fracture risk.

Bones develop by one of two processes, either:

Subsequent skeletal growth involves remodelling of bone. In the growing skeleton, the long bones consist of a diaphysis (or shaft) separated from the ends of the bone (called the epiphyses) by cartilage. The part of the diaphysis immediately adjacent to the epiphysial cartilage is the site of advancing ossification and is known as the metaphysis. Endochondral ossification is a complex process in which the growth plate cartilage is progressively replaced by bone. The growth plate (physis) and bone front steadily advance away from the bone centre, resulting in progressive elongation of bone. Longitudinal growth continues while the growth plate remains open.

Growth plates start to close after puberty in response to the surge in circulating oestrogen. Several hormones including growth hormone, insulin-like growth factor-1 (IGF-1) and PTHrP play a role in bone growth. With growth throughout early childhood, bone size and mass gradually increase in a linear fashion. Then between the onset of puberty and young adulthood, skeletal mass approximately doubles. Most of the increase in bone mass in early puberty is due to increases in bone size. In cortical bone, both the inner (endocortical) and outer (periosteal) diameters increase, owing to enhanced resorption and apposition on these surfaces respectively. Gains in bone mineral density during puberty are dependent on the pubertal stage.

Growth ceases when closure of the growth plate occurs, but bone mass and density may continue to increase beyond this time by a process called consolidation. The maximum skeletal mass achieved is termed the peak bone mass. The age at which this is attained varies in different skeletal sites.