Bone and mineral metabolism

Herbert Fleisch

1.1 Bone physiology

1.1.1 Morphology

Macroscopically, bone can be divided into an outer part called cortical or compact bone, which makes about 80% of the total skeleton, and an inner part named cancellous, trabecular, or spongy bone. This structure, an outer cortical sheath and an inner three-dimensional trabecular network, allows optimal mechanical function under customary loads.

Microscopically, woven and lamellar bone can be distinguished. Woven bone is the type formed initially in the embryo and during growth, and is characterized by an irregular array of loosely packed collagen fibrils. It is then replaced by lamellar bone, so that it is practically absent from the adult skeleton, except under pathological conditions of rapid bone formation, such as occur in Paget’s disease, fluorosis, or fracture healing. In contrast, lamellar bone is the form present in the adult, both in cortical and in cancellous bone. It is made of well-ordered parallel collagen fibers, organized in a lamellar pattern.

Bone is made of basic units called bone structural units (BSUs). In cortical bone these are called osteons or Haversian systems, which represent its basic structural building blocks. These are hollow cylinders of a median length of 2 mm, but which can reach 8 mm, and 200 μm in diameter, made of concentric lamellae, between which the osteocytes are located. In the center is a canal containing the nutrient blood vessels. These anastomose with vessels from other osteons so that the various osteons are in communication with one another. The diameter of the osteon is always about 200 μm, regardless of species, the maximal distance of any part from the central vessel being no more than 100 μm, this being the largest transport distance for nutrients. Osteons are separated from one another by so-called cement lines.

The trabeculae also consist of structural units, which in this location are called packets. They are separated, as are the osteons of the cortex, by cement lines. When they are on the surface and not yet terminated, they are called bone multicellular units (BMUs). However, BMUs and packets are also found on the inner surface of the cortex, which therefore looks very much like trabecular bone. These two locations, trabeculae and inner cortex, are those that are affected predominantly by osteoporosis.

Trabeculae generally possess no vessels and are therefore nourished from the surface. This explains why they cannot become much thicker than about 200–300 μm, twice the distance of 100 μm over which transport of nutrients is possible.

1.1.2 Composition of bone

Bone is made up of mineral, a fibrillar organic matrix, cells, and water.

Mineral

Mineral accounts for about two-thirds of the total dry weight of bone. It is made of small crystals of about 200−400 Å × 35−75 Å × 10−40 Å in the shape of plates, located within and between the collagen fibrils. Chemically it is a calcium deficient apatite, containing, however, many other constituents, among others HPO4−, carbonate, citrate, magnesium, sodium, fluoride, and strontium. These are either incorporated into the crystal lattice, or adsorbed onto the crystal surface. For this reason, the more general term calcium phosphate will be used in this book for bone mineral.

Some substances, such as tetracyclines, polyphosphates, and bisphosphonates, have a special affinity for calcium phosphate and hence for bone. They are deposited in preference on the mineral at sites of new bone formation, but can also be deposited at other sites such as resorption areas. This bone seeking property has been utilized in the case of tetracyclines in order to label newly formed bone, thus enabling the assessment of bone formation. Indeed, by administering tetracycline, a fluorescent molecule, twice or more at known time intervals, it is possible to measure in bone biopsies the distance between the two lines of deposition of the fluorochrome, thus enabling the quantification of the bone formed during the time interval. The binding of polyphosphates and bisphosphonates, when linked to 99mTc, is used in nuclear medicine to visualize hot spots of bone formation by scintigraphy. This technique is especially useful for detecting skeletal metastases and the bone lesions in Paget’s disease. Lastly, the strong binding of bisphosphonates to bone mineral is fundamental to their pharmacological activity. The binding of these substances is usually reversible at sites where the bone surface is accessible to the extracellular fluid. However, it is irreversible at sites which become buried by new bone formation, until the bone with the bone seeker is destroyed again during modeling or remodeling.

The mineral crystals are deposited within and between the collagen crystals in a manner which gives the bone tissue its compressive strength and stiffness. The process of mineralization proceeds rapidly initially, to proceed subsequently over months and years with decreasing speed, a process called secondary mineralization. This property explains why old bone is more mineralized and has a higher mineral density when measured by DXA than a younger one, and why a decrease in bone turnover is accompanied by an increase in bone density.

The mineralization process is under the modulation of both activators and inhibitors. Thus, the collagen fibrils themselves as well as other proteins can act as activators, while pyrophosphate and proteins such as matrix gla-protein can act as inhibitors.

Organic matrix

The matrix amounts to about 35% of the dry weight of bone. It consists of 90% collagen, which is thus by far the most abundant bone protein. Its complex three-dimensional structure, comparable to that of a rope, gives bone tissue its tensile strength.

The remainder of the bone matrix is made up of various noncollagenous proteins, the role of which is not yet well understood. The most abundant are osteonectin, osteocalcin, previously called bone gla-protein (BGP), osteopontin, and bone sialoprotein. Because some of them are synthesized and deposited almost exclusively in bone, their urinary excretion and plasma or serum levels are used clinically to assess bone turnover.

The organic matrix also contains a large amount of various growth factors, especially transforming growth factor β (TGFβ) and insulin-like growth factor II (IGF II). These are thought to play a role after their release during bone resorption in the local modulation of bone formation during the turnover of the BSUs, and in the growth of tumor cells in bone metastases.

Bone cells

Osteoblasts

The osteoblasts, which derive from mesenchymal progenitors, are the cells that synthesize the bone matrix. They form an epithelial-like structure at the surface of the bone and are connected by gap junctions containing connexins. These and the cell adhesion molecules of the Cadherin super-family are thought to play an essential role in the control of osteoblast formation and function. The osteoblasts secrete unidirectionally the osseous organic matrix which, in a second step, then calcifies extracellularly. As a consequence of the time lag between the formation of the matrix and its calcification, there is a layer of unmineralized matrix osteoid under the osteoblasts. This osteoid seam diminishes in width when the rate of bone matrix formation...