BONE REMODELLING AND TYPES OF BONE

Bone : Highly organized, living tissue and is the major constituent of the skeleton. Reservoir for inorganic ions, bone is responsible for the maintenance of calcium homeostasis and is able to rapidly mobilize mineral stores on metabolic demand

It is a mineralised tissue consisting 28% type 1 collagen and 5% noncollagenous, structural matrix proteins such as bone sialoprotein, osteocalcin, osteonectin, osteopontin and proteoglycans; growth factors and serum proteins and 67% inorganic matrix consisting of calcium and phosphorous appearing as hydroxyapetite crystals deposited into the collagenous matrix.

Bone cells are responsible for formation, resorption and maintenance. Osteogenic cells, osteoblasts and hormones play an important role.

Osteogenic cells have a variable morphology, including osteoprogenitors, preosteoblasts, osteoblasts, osteocytes, and bone lining cells.

Osteoblasts are mononucleated cells that synthesize collagenous and noncollagenous bone matrix proteins; some of these constituents first accumulate as an uncalcified matrix called osteoid composed of collagen which acts as scaffold for deposition of apatite crystals of bone. Though osteoblasts are differentiated cells, both preosteoblasts and osteoblasts can undergo mitosis during prenatal and sometimes during post natal development. Both cells exhibit high levels of alkaline phosphatase activity.

Osteoblasts : Are plump cuboidal cells when active or slightly flattened which are responsible for production of organic matrix of bone.

Type 1 collagen is the dominant component with small amounts of type 5 collagen and proteoglycans and several non collagenous proteins.

Hormones most imp in bone metabolism : Parathyroid hormone, 1,25-dihydroxy vitamin D, calcitonin, estrogen and glucocorticoids. Actions of PTH and Vit D are dual, enhancing bone resorption at high (pharmacologic) conc but supporting bone formation at lower (physiologic) conc. Calcitonin and estrogen inhibit resorption, whereas glucocorticoids inhibit resorption and formation. The hormones affecting bone most likely work primarily through altering the secretion of cytokines and growth factors.

Leptin, a circulating hormone produced by adipocytes that is involved in regulating food intake and body weight, has been proposed also to control bone mass. This hormone acts on hypothalamus and through involvement of sympathetic nervous system can promote and inhibit the differentiation of osteoclasts. Some evidence also indicates that leptin also works locally to promote differentiation of osteoprogenitor cells and stimulate osteoblasts.

Osteoblasts, bone lining cells, osteocytes and osteoclasts :

Osteoblasts : form a cell layer over the forming bone surface and have been proposed to act as a barrier that controls ion flux into and out of bone. Although there are no junctional complexes between cells, gap junctions do form and functionally couple adjacent cells.

When bone is no longer forming, osteoblasts flatten substantially, extending along the bone surface, termed as bone lining cells that contain few synthetic organelles, suggesting that they are less implicated in production of matrix proteins. They cover most surfaces in adult skeleton. Bone lining cells retain their gap junctions with osteocytes, creating a network that functions to control mineral homeostasis and ensure bone vitality.

Osteocytes : As osteoblasts form bone, some become entrapped within the matrix they secrete, whether mineralized or unmineralized; these cells then are called osteocytes. The number of osteoblasts that become osteocytes varies depending on the rapidity of bone formation; more rapid the bone forms more osteocytes are present per unit volume. As a general rule, embryonic (woven) bone and repair bone have more osteocytes than lamellar bone.

After their formation, osteocytes become reduced in size. Space in the matrix occupied by an osteocyte is called osteocytic lacuna. Narrow extensions of these lacunae form enclosed channels, or canaliculi, that house radiating osteocytic processes. Through these channels, osteocytes maintain contact with adjacent osteocytes and with the osteoblasts or lining cells on the bone surfaces. This places osteocytes in an ideal position to sense biochemical and mechanical environments and transduce signals for maintaining bone integrity and vitality. Although osteocytes gradually reduce most of their matrix synthesizing machinery, they still are able to secrete matrix proteins.

Osteoclasts : multinucleated and large cell, often seen in clusters. Characterized cytochemically by possessing tartrate-resistant acid phosphatase within its cytoplasmic vesicles and vacuoles, which distinguishes it from multinucleated giant cells. Typically osteoclasts are found against the bone surface, occupying hollowed out depressions called Howship’s lacunae that they have created. Howship’s lacunae are shallow troughs with an irregular shape, reflecting activity and mobility of osteoclasts during active resorption. Adjacent to the tissue surface, the cell membrane of osteoclast is thrown into a myriad of deep folds that form a ruffled border. At the periphery of this border, the plasma membrane is apposed closely to the bone surface; and the adjacent cytoplasm, devoid of cell organelles, is enriched in actin, vinculin, and talin, proteins associated with integrin-mediated cell adhesion. This clear or sealing zone not only attaches the cells to the mineralized surface but also isolates a microenvironment between them and the bone surface. Several mechanisms bind the osteoclast to surfaces; among these, molecules like bone sialoprotein and osteopontin on bone surfaces may facilitate osteoclast adhesion and formation of the sealing zone by means of an αvβ3 mediated mechanism. Another feature of osteoclasts is a proton pump associated with ruffled border that pumps hydrogen ions into the sealed compartment.

Bone remodelling : Basic principles and current concepts

Adult bone mass represents the end result of two processes; acquisition of peak bone mass during adolescence and maintenance of bone density during the middle and later years. Changes in bone mass result from physiologic and pathophysiologic processes in the bone remodeling cycle. This can occur during the stage of accelerated linear growth in adolescence, or much later in life, usually after menopause in women. The bone remodeling cycle is a tightly coupled process whereby bone is resorbed at approximately the same rate as new bone is formed. Basic multicellular units (BMUs) compose the remodeling unit of bone and include: osteoclasts which stimulate bone resorption, osteoblasts, which are responsible for new bone formation, and osteocytes, older osteoblasts surrounded by bone and present in a reduced state of activity. Activation of the remodeling cycle serves two functions in the adult skeleton: 1) to produce a supply rapidly, as well as chronically, of calcium to the extracellular space; 2) to provide elasticity and strength to the skeleton. When the remodeling process is uncoupled so that resorption exceeds formation, bone is lost. On the other hand, during peak bone acquisition, formation exceeds resorption resulting in a net gain of bone. Remodeling is more pronounced in the trabecular skeleton (e.g. spine, calcaneus and proximal femur) and is the most metabolically active component of bone, in part because of its proximity to the marrow space. However, trabecular bone is also extremely vulnerable to perturbations by local or systemic factors that can cause significant imbalances in bone turnover.

Process by which the overall size and shape of bones is established is referred to as bone modeling and extends from embryonic bone development to the preadult period of human growth. During this phase bone is being formed rapidly, primarily on periosteal surface. Simultaneously, bone is being destroyed along the endosteal surface at focal points along the periosteal surface and within the osteons of compact bone. Because bones increase greatly in length and thickness during growth, bone formation occurs at a much greater rate than bone resorption. This replacement of old bone by new is called bone turnover or remodeling.

Bone turnover rates of 30% to 100% per year are common in rapidly growing children. Bone turnover does not stop when adulthood is reached, although its rate slows. Indeed the adult skeleton is broken down continuously and reformed by the co-ordinated action of osteoblasts and osteoclasts. In health, this turnover is in a steady state; that is, the amount of bone lost is balanced by bone formed. In certain diseases (Osteoporosis) and with age, resorption exceeds formation, resulting in overall loss of bone.

• Bone formation and resorption : Coupled

• Resorptive phase : 3 to 4 week period

• Formative phase : 3 to 4 month period for one unit called the BMU (Basic multiceelular unit)

• Reversal phase : Cells that appear morphologically inactive line the resoption lacunae

• Adult skeleton : More than 1 million BMUs at any time, with nearly 5-fold more in trabecular versus cortical bone

• Osteoblasts : Derived from mesenchymal precursor cells

• Precursor cells differentiate into preosteoblastic cells through action of BMPs and growth factors

• Lifespan of osteoblast : 3 months

Osteoclasts : Derived from hematopoietic lineage

Characteristic features

• TRAP enzyme

• 3 or more nuclei per cell

• Ruffled membrane and clear zone

• Proton pump

• 2 molecules considered essential to support osteoclastogenesis

• M-CSF or CSF-1

• RANKL

Process of resorption is initiated with a resorptive stimulus through activation of M-CSF or RANKL although in pathologic states, mediators such as TNF-α and IL-1 may act independently of RANKL.

Key early event in bone resorption : Attachment of osteoclast to bone matrix, mediated by αvβ3 integrins and formation of sealing zone that enables the osteoclast to isolate a microenvironment beneath it to facilitate resorption.

Activated osteoclast : Creates acidic environment beneath it via H+ -ATPase activity of the ruffled membrane proton pump, responsible for dissolving the mineral component of the matrix.

Secretion of HCl into the resorptive microenvironments result in a pH of 4.5 necessary for mobilization of the bone mineral. Organic component is degraded by MMPs and cathepsin K. Osteoclasts likely undergo repeated cycles of resorption in an area and then move to new site to evoke another cycle of resorption or undergo apoptosis and hence cease resorption.

RANKL (also known as OPG ligand or TRANCE) is a cell surface protein present on osteoblastic cells and is responsible for osteoclast differentiation and bone resorption. RANKL interacts with its

receptor, RANK, on hematopoietic cells, an interaction thought to be essential for osteoclast activation. In the absence of RANKL, osteoclastic resorption is reduced and increases in bone mass occur.

There are relatively fewer ihibitors of bone resorption than stimulators. A soluble factor, OPG binds to RANKL and inhibits the differentiation of osteoclasts. OPG is being explored in human clinical trials for the treatment of osteoporosis, metastatic bone disease and also in animal models of rheumatoid arthritis and periodontal disease.

Interferon γ is a cytokine produced by activated T lymphocytes that inhibits bone resorption by inhibiting the differentiation of committed precursors to mature cells.

Systemically, calcitonin is a potent inhibitor of bone resorption but, in pharmacologic use, has limited application since patients become refractory to its inhibitory action.

Estrogen is another systemic hormone that inhibits bone resorption as evidenced by the increase in osteoporosis with estrogen deficiency after menopause. Although its mechanisms of action are not clear, it is thought to promote programmed cell death of osteoclasts and hence reduce their period of activity.

Bone classification schemes related to implant dentistry

Linkow’s classification of bone density (1970)

• Class 1 bone structure : This ideal bone type consists of evenly spaced trabeculae with small cancellated spaces.

• Class 2 bone structure : The bone has slightly larger cancellated spaces with less uniformity of the osseous pattern.

• Class 3 bone structure : Large marrow filled spaces exist between bone trabeculae.

Lekholm and Zarb (1985)

• Quality 1 : Composed of homogeneous compact bone

• Quality 2 : Thick layer of compact bone surrounding a core of dense trabecular bone

• Quality 3 : Thin layer of cortical bone surrounding dense trabecular bone of favorable strength

• Quality 4 : Thin layer of cortical bone surrounding a core of low density trabecular bone

Misch’s classification (based on bone density )

• D1: Dense cortical bone

• D2: Thick dense to porous cortical bone on the crest and coarse trabecular bone within.

• D3: Thin porous cortical bone on crest and fine trabecular bone within.

• D4: Fine trabecular bone

• D5: Immature, non-mineralized bone