Chapter 2

Bone Physiology and Metabolism

Jean-Pierre Dibart, MD

BONE COMPOSITION

Bone consists of three types of cells and a matrix.

Cells: Osteoblasts, Osteoclasts, and Osteocytes

Osteoblasts and osteocytes (mature osteoblasts) are involved in the deposition of bone matrix. Osteoblasts are responsible for the formation of new bone; they secrete osteoid and modulate the crystallization of hydroxyapatite. Osteocytes are mature bone cells; they communicate with each other via gap junctions or canaliculi. Osteoclasts are involved in the resorption of bone tissue; they are responsible for the resorption of bone, which is necessary for its repair in case of fracture or remodeling.

Matrix: Organic and Inorganic

The organic matrix is composed of collagen fibers and a ground substance. The collagen fibers are proteins that give bone its flexibility. The ground substance is made of proteoglycans and glycosaminoglycans: keratin sulfate, chondroitin sulfate, and hyaluronic acid. These components bind cells together and are necessary for the exchange of materials.

The inorganic matrix is composed of hydroxyapatite, calcium carbonate, and calcium citrate. Hydroxyapatite gives bone its strength. Hydroxyapatite is a very hard substance; it is the main mineral component of bone and the enamel of teeth, and it contains calcium, phosphorus, oxygen, and hydrogen.

Bone is the body’s major reservoir of calcium (the skeleton contains 99% of the body’s calcium, as hydroxyapatite). Mature adults have about 1200 g of calcium.

BONE TYPES

There are two different types of bone:

• Cortical bone, also known as compact bone
• Trabecular bone, also known as cancellous bone

Cortical Bone

Denser and more calcified than trabecular bone, cortical bone is found in the diaphysis of long bones and in the exterior of short bones. It is also called compact bone, and it has a high resistance to bending and torsion. Osteons (Haversian system) are the predominant structures found in compact bone. Each osteon is composed of a central vascular channel, the Haversian canal, surrounded by concentric layers of matrix called lamellae. Osteocytes are found between concentric lamellae. They are connected to each other and the central canal by cytoplasmic processes through the canaliculi. Osteons are separated from each other by cement lines. The space between separate osteons is occupied by interstitial lamellae. Osteons are connected to each other and the periosteum by oblique channels called Volkmann’s canals (Marieb 1998).

Trabecular Bone

Trabecular bone is more spongy than cortical bone, it has a lower calcium content and a higher turnover rate, and it is more vulnerable to bone loss. It is found at the metaphysis and diaphysis of long bones and in the interior of the short bones (spine). It is composed of bundles of short and parallel strands of bone fused together. The external layer of trabecular bone contains red bone marrow, where the production of blood cellular components takes place and where most of the arteries and veins of bone organs are located (Tortora 1989).

BONE FORMATION

Intramembranous and Endochondral Ossifications

• Intramembranous ossification: Direct replacement of connective tissue with bone (i.e., mandible and flat bones of the skull)
• Endochondral ossification: Cartilage is replaced by mineralized bone, and the bones become longer, explaining growth during childhood (i.e., femur and humerus).

Bone Remodeling

Remodeling is a sequence of activation, resorption, and formation. The bone is continuously remodeling; osteoclasts become activated and resorb the old bone, and then osteoblasts begin formation of the new bone, giving rise to the Haversian system. The mature osteoclasts resorb bone by forming a space on the matrix surface; then, the osteoids begin to mineralize, regulated by the osteoblasts.

Months later, the crystals are packed closely, and the density of the bone increases.

Remodeling is necessary to maintain bone structure after a fracture or after age-related modifications; osteoclasts resorb aging bone in order to repair damage and maintain the quality of bone and to retain calcium homeostasis.

Bone can also remodel according to stresses, such as orthodontic tooth movement, in which there is resorption on the pressure side and apposition on the traction side.

Complete rest results in accelerated bone loss, whereas weight-bearing activities are associated with bone formation. Peak bone mass is the maximum bone mass achieved by midlife. Exercise programs increase bone mass at all ages; adolescence is a particularly critical period because the velocity of bone growth doubles. When women reach menopause, bone resorption exceeds bone formation, osteoblastic activity cannot keep up with osteoclastic activity, and women begin to lose bone. This puts them at high risk for osteoporosis and fractures.

There are five stages in bone remodeling:

1. Quiescence: Resting state of the bone surface

2. Activation: Recruitment of osteoclasts to a bone surface; osteoblasts secrete collagenase

3. Resorption: Removal of bone by osteoclasts; Howship’s lacunae are excavated

4. Reversal: Short phase; cement line is formed; osteoclasts stop removing bone; osteoblasts fill the defect

5. Formation: Laying down of bone; osteoblasts produce osteoid; mineralization begins; then bone is again converted to a resting surface

Bone is remodeled through the following actions:

• Osteoblasts
• Osteoclasts
• Parathyroid hormone (PTH)
• Vitamin D
• Calcitonin (CT)
• Estrogens
• Corticoids
• Growth hormone (GH)
• Thyroid hormone

Bone Remodeling and Periodontitis

After damage to the bone has occurred, the osteocytes send messages to the surface to produce preosteoblasts. They express RANK-L (receptor activator of nuclear factor [NF]-κB ligand). Preosteoclasts have receptors called RANK (receptor activator of NF-κB). RANK-ligand (RANK-L) activates these receptors, which produce mature osteoclasts. RANK, RANK-L, and osteoprotegerin (OPG) (RANK-L inhibitor) are the key factors regulating osteoclast formation in normal bone physiology. The molecular interactions of these molecules regulate osteoclast formation and bone loss in various diseases such as rheumatologic inflammatory diseases, periodontitis, or peri-implantitis (Haynes 2004). The change in the levels of these regulators plays a role in the bone loss seen in periodontitis. Significantly higher levels of RANK-L protein were found to be expressed in the periodontally affected tissues, whereas OPG protein levels are lower. RANK-L protein is associated with lymphocytes and macrophages; many leukocytes expressing messenger RNA (mRNA) are observed in periodontitis tissues (Crotti et al. 2003). RANK-L is a TNF (tumor necrosis factor) receptor– related protein and a major factor for osteoclast differentiation and activation. The levels of RANK-L mRNA are higher in advanced periodontitis; although the levels of OPG mRNA are lower in advanced and moderate periodontitis, the ratio of RANK-L to OPG mRNA is increased in periodontitis. RANK-L mRNA is expressed in proliferating epithelium and in inflammatory cells, mainly lymphocytes and macrophages. Upregulation of RANK-L mRNA is associated with the activation of osteoclastic bone destruction in periodontitis (Liu et al. 2003).

Markers of Bone Formation

Markers of bone formation measure osteoblastic activity: osteocalcin, P1NP (N-terminal propeptide of type 1 procollagen), and bone-specific alkaline phosphatase (BALP).

Markers of Bone Resorption

These markers measure osteoclastic activity: deoxypyridino-line (DPD), pyridinoline and associated peptides, NTX (cross-linked N-terminal telopeptide of type I collagen), and CTX I (cross-linked C-terminal telopeptide of type I collagen) generated from bone by osteoclasts as a degradation product of type I collagen and released into circulation.

Vitamin C

This vitamin is necessary for the osteocytes to form collagen; in the case of vitamin C deficiency, collagen formation is decreased, and so is the thickness of the bone cortex.

Vitamin D

It has an important role in calcium absorption. The two major forms involved in humans are vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). 1,25-Dihydroxy-vitamin D₃ [1,25-(OH)2 vitamin D₃] is produced by metabolism in the liver and the kidneys. It is the most active form of vitamin D, and it increases calcium absorption from the intestines. Conversion into the active metabolite 1,25-(OH)2 vitamin D₃ from its precursor is affected by cytochrome P450 enzymes in the liver and the kidneys. This is tightly regulated by the plasma levels of calcium, phosphate, PTH, and 1,25-(OH)2 vitamin D₃ itself (Tissandie et al. 2006). It affects the kidneys and the intestines and stimulates the mineralization of bone. Ultraviolet irradiation from the sunlight to the skin will also affect the production of vitamins D₂ and D₃.

Genetic polymorphisms in the vitamin D receptor (VDR) gene are associated with parameters of bone homeostasis and with osteoporosis and rapid bone resorption. Interestingly, some authors have found VDR polymorphism to be associated with localized aggressive periodontal disease (Hennig et al. 1999)

Childhood vitamin D deficiency syndrome is called rickets: unmineralized osteoid accumulates, and the bone formed is weak and can lead to permanent deformities of the skeleton. In adulthood, the absence of adequate amounts of vitamin D leads to osteomalacia: decalcification of bone occurs by defective mineralization of newly formed bone matrix.

What are the sources of vitamin D? Only a few foods contain appreciable amounts of vitamin D—fish liver, fish (i.e., salmon, mackerel, tuna, sardines), eggs, liver, butter, and Shii-take mushrooms.

Vitamin K

This vitamin is required for the production of osteocalcin (a protein produced by the osteoblasts); a good vitamin K status is necessary to prevent osteoporosis. Vitamin K is found in green leafy vegetables.

Calcitonin

This is a hormone secreted by the thyroid gland. Its effects are opposite those of the PTH (lowering of blood calcium)./>