1- Bone remodeling.pdf

Bone structure & remodeling Bone structure: I. Minerals (70%): Hydroxypatite (95%) Hydroxypatite is a crystalline salts though may be present in amorphous forms Hydroxypatite deposited in the organic matrix of bone and teeth Hydroxypatite are composed principally of calcium and phosphate {Ca10 (...

Bone structure & remodeling Bone structure: I. Minerals (70%): Hydroxypatite (95%) Hydroxypatite is a crystalline salts though may be present in amorphous forms Hydroxypatite deposited in the organic matrix of bone and teeth Hydroxypatite are composed principally of calcium and phosphate {Ca10 (PO4)6(OH) 2} Hydroxypatite crystals are platelets or rods, about 8 to 15A thick, 20 to 40A wide and 200 to 400A long. Hydroxypatite relative ratio of calcium to phosphorus can vary markedly under different nutritional conditions, with the calcium to phosphorus ratio on a weight basis varying between 1.3 and 2.0. Magnesium, sodium, potassium, and carbonate ions are also present among the bone salts, although x-ray diffraction studies fail to show definite crystals formed by them. Therefore, they are believed to be conjugated to the hydroxyhydroxyapatite crystals rather than organized into distinct crystals of their own. This ability of many types of ions to conjugate to bone crystals extends to many ions normally foreign to bone, such as strontium, uranium, plutonium, cesium the other transuranic elements(chemical elements with atomic numbers greater than 92, which is the atomic number of uranium),and also lead, gold, and other heavy metals. Deposition of radioactive substances in the bone can cause prolonged irradiation of the bone tissues, and if a sufficient amount is deposited, an osteogenic sarcoma (bone cancer) may eventually develop. II. Organic (30%) Matrix of Bone (98%). The extracellular matrix functions in holding all the cells of a tissue in their place. The extracellular matrix consists of two major substances: ground substances (Proteoglycans are a type of ground substances) fibrous proteins (collagen are a type of fibrous proteins) 1) Collage type I (90%) Type I collagen, is the major structural protein in bone, tendons ,skin, cornea, blood vessel wall and other connective tissues Type I collagen, which weight for weight is as strong as steel Type I collagen, is made up of a triple helix of three polypeptides bound tightly together. The collagen fibers of bone, like those of tendons, have great tensile strength, whereas the calcium salts have great compressional strength. These combined properties plus the degree of bondage between the collagen fibers and the crystals provide a bony structure that has both extreme tensile strength and compressional strength. Type I collagen fibers extend primarily along the lines of tensional force and give bone its powerful tensile strength. 2) Non-Collagenous Proteins I. Phosphoproteins include A. bone proteoglycans Proteoglycans consist of glycosaminoglycan (GAG) and hyaluronic acid Glycosaminoglycan consist of chondroitin sulfate and core protein. Glycosaminoglycan make about 95% of the weight of proteoglycans Functions of glycosaminoglycan a. They have the special ability to bind large amounts of water, there by producing the gel-like matrix that forms the basis of the body’s ground substance. The bone matrix has a lower proteoglycan content than those in the cartilage. This is the reason bones take up less quantity of water and are, thus, more brittle ‫جاف‬. b. Since glycosaminoglycan are negatively charged in the bone glycosaminoglycan attract and tightly bind cation like calcium and sodium and potassium. c. glycosaminoglycan bind tightly to hydroxyapatite which would protect hydroxyapatite molecules from the destructive effects of temperature and chemical agents after death (Proteoglycans inhibit calcification by masking the collagen fibrils or occupying critical spaces within the fibril and thereby diminishing diffusion, chemical interaction and sequestration ‫حجز‬calcium ions or calcium phosphate complexes) Small leucine-rich proteoglycans (SLRPS) are the major bone glycoproteins Small leucine-rich proteoglycans are a large family of proteins characterized by a. core proteins with leucine-rich repeats (LRR), and b. at least one glycosaminoglycan side chain Small leucine-rich proteoglycans include at least 4 classes (e.g. decorin, biglycan, keratocan, fibromodulin, epiphycan). B. Osteocalcin also known as bone γ-carboxyglutamic acid-containing protein (BGLAP) Osteocalcin is the most abundant non-collagenous protein in bone Osteocalcin comprising about 20% of the non-collagen matrix proteins and Osteocalcin produced by osteoblasts. Osteocalcin contains three γ-carboxylglutamic acid (Gla) residues that bind calcium Osteocalcin vitamin K-dependent. Osteocalcin functions: Osteocalcin has been postulated that it could retard calcification Osteocalcin is a chemoattractant for osteoclasts.  Osteocalcin like alkaline phosphatase is used i. clinically as osteoblast activity marker ii. serum osteocalcin as bone turnover marker. C. Matrix Gla Protein (MGP) γ-carboxylglutamic acid (Gla) Matrix Gla Protein is a possible regulator of extracellular matrix calcification Matrix Gla Protein, like osteocalcin, is a member of the vitamin K-dependant γ- carboxylglutamic acid (Gla) proteins D. Alkaline phosphatase is an ecto-enzyme produced by osteoblasts E. Lipid and proteolipids II. Cell Attachment Proteins Cell attachment proteins have the common RGD amino acid sequence (arginin-glycin-aspartic acid), which is responsible for mediating attachment of these proteins to integrins (integral membrane proteins) on the cell surface. A. Osteopontin Osteopontin is relatively abundant non-collagenous sialoprotein Osteopontin is produced by osteoblasts. Osteopontin increasing intracellular calcium Osteopontin has calcium binding sites. Osteopontin increases vitamin D secretion Osteopontin binds to integrin receptors on the osteoclast by its RGD sequence Osteopontin bone resorption Osteopontin activating the phospholipase C pathway in the osteoclast B. Osteonectin Osteonectin is an acidic glycoprotein Osteonectin is involved in cell attachment. Osteonectin supports bone remodelling. Osteonectin maintenance of bone mass in vertebrates Osteonectin is synthesized by bone osteoblasts, skin fibroblasts, tendon cells odontoblasts Osteonectin binds to type I collagen and hydroxyapatite ( reported to promote crystal growth in vitro). Osteonectin increases the production and activity of matrix metalloproteinases, a function important to invading cancer cells within bone C. Fibronectin Fibronectin is a ubiquitous‫ واسع االنتشار‬cell attachment protein Fibronectin made a. locally by bone cells or b. synthesized elsewhere and brought into bone by the vasculature. Fibronectin coordinate the migration, interaction and differentiation of osteoblast precursors in vitro and in vivo D. Thrombospondin Thrombospondin contains calcium binding sites in addition to the RGD sequence. Thrombospondin mediates cell attachment, but any particular function in bone remains unknown E. Bone sialoprotein (BSP), Bone sialoprotein is present unique to in the skeleton, component bone dentin & cementum and calcified cartilage Bone sialoprotein may act as a nucleus for the formation of the first hydroxyapatite crystals along the collagen fibers within the extracellular matrix,  Bone sialoprotein could then help direct, redirect or inhibit the crystal growth. Bone sialoprotein providing cell attachment Bone sialoprotein is a significant component of the bone extracellular matrix and Bone sialoprotein has been suggested to constitute approximately 8% of all non-collagenous proteins found in bone and cementum. Bone sialoprotein are angiogenesis and protection from complement-mediated cell lysis. III. Regulatory Growth Factors in Bone A. Transforming growth factor β (TGFβ) including transforming growth factor βI (TGFβI), and TGFβII B. Fibroblast growth factors (FGFs) C. Bone morphogenetic proteins (BMPs) or osteogenic proteins D. Insulin-like growth factors (IGFs), IGF-I and IGF-II, are proteins with high sequence similarity to insulin. Insulin-like growth factors are present in the circulation Insulin-like growth factors synthesized by many tissues, including bone, where they act similarly as local regulators of cell metabolism. In bone IGF-I is more potent than IGF-II Insulin-like growth factors functions a. Insulin-like growth factors associated with bone growth b. Insulin-like growth factor-I stimulates IGE i. mitogenesis ii. collagen synthesis iii. infusion causes a generalized anabolic effect and an increase in bone remodelling E. Platelet-derived growth factor (PDGF) F. Colony stimulating factor (CSF) also called monocyte-macrophage colony stimulating factor (M-CSF) G. Lymphotoxin and tumor necrosis factor (TNF) H. Prostaglandins ii. Cellular component A. Osteoblasts: Osteoblasts are modified fibroblasts. Osteoblasts early development from the mesenchyme is the same as that of fibroblasts, with extensive growth factor regulation; RUNX2 (also known as CBFA1), contribute to their differentiation and as a master regulator of bone development. Osteoblasts are able to lay down type 1 collagen and Osteoblasts are able to form new bone matrix (osteoid) Osteoblasts found on the surface bone so responsible for growth in thickness of long bones Osteoblasts control mineralization ¥"" Osteoblasts can initiate bone resorption B. osteoclasts: primary Osteoclasts responsible for bone resorption Osteoclasts, which are function large, phagocytic, multinucleated cells (containing as many as ✓ 50 nuclei), abundant mitochondria and a large number of vacuoles and lysosomes) Osteoclasts are derivatives of monocytes or monocyte-like cells formed in the bone marrow. The osteoclasts are normally active on less than 1 percent of the bone surfaces of an adult. Bone remodeling Bone is continually being resorbed where osteoclasts are active and is continually being deposited by osteoblasts (bone deposition). This mechanism called bone remodeling which is always is in balance. Any disturbance of this mechanism ill causes a disease. For example, increase osteocyte activity (bone resorption) will causes osteoporosis. In Paget's disease, osteoclasts are more active than osteoblasts. This means that there is more bone absorption than normal. The osteoblasts try to keep up by making new bone, but they overreact and make excess bone that is abnormally large, deformed, and fits together haphazardly ‫عشوائي‬ Osteoblasts are found on the outer surfaces of the bones and in the bone cavities. A small amount of osteoblastic activity occurs continually in all living bones (on about 4 percent of all surfaces at any given time in a constantly. How osteoclast stimulated Resorption of Bone—Function of the Osteoclasts. 1α 25(OH)2 D3 through Vitamin D3, Parathyroid hormone, Prostaglandin E2 and Interleukin-11, Interleukin-1β, TNFα will Osteoblast secret three materials stimulate osteoblastic cell (increase RANKL production) then  receptor activator for nuclear factor κ-B ligand (RANKL) Osteoblasts express two cytokines essential for osteoclast  macrophage colony-stimulating factor (M-CSF) differentiation: a. RANKL (Receptor Activator of Nuclear Factor-Kappa B  osteo-protegerin (OPG), sometimes called osteo-clasto- Ligand) genesis inhibitory factor b. M-CSF (Monocyte- colony stimulating Factor)  Osteoclast precursor will bind to receptor activator where a. nuclear factor κ-B ligand (RANKL) bind to receptor activator for nuclear factor κ-B (RANK) b. macrophage colony-stimulating factor (M-CSF) bind to macrophage colony-stimulating factor (M-CSF) receptor which is c-Fms The above activation will differentiate Osteoclast precursors into pre-osteoclasts  Many pre-osteoclast meat together forming one large multinucleated mature osteoclast  Osteoblastic cell will be activated when RANK of Osteoclast cell will join (RANKL receptor) of osteoblastic cell. The mature osteoclasts then develop a ruffled border and release enzymes and acids that promote bone resorption Step 1,2,3 is called differentiation while step 4 and 5 is activation. Osteoclastogenesis process some define it as differentiation and activation processes (activation of the receptor activator of nuclear factor κB (RANK) in osteoclast precursors induced by RANK ligand (RANKL), which is produced mainly by osteoblastic cells) How osteoclast inhibited Many factors as 17-β oestradiol, 1,25(OH)2 D3, Interlukin-1, Tumor necrotic factor-β, calcitonin all will stimulate osteoblastic cell to produce Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) while PGE2 inhibit it. OPG binding to RANKL on osteoblastic cell, blocks the RANKL-RANK interaction between osteoblast cells and osteoclast precursors. This has the effect of inhibiting the differentiation of the osteoclast precursor into a mature osteoclast. The therapeutic importance of the OPG-RANKL pathway is currently being exploited. Novel drugs that mimic the action of OPG by blocking the interaction of RANKL with its receptor appear to be useful for treating bone loss in postmenopausal women (osteoporosis) and in some patients with bone cancer. Bone deposition and resorption are normally in equilibrium. Mechanism of osteoclast mediated bone resorption Histologically, bone absorption occurs immediately adjacent to the osteoclasts. Osteoclasts erode and absorb previously formed bone. Osteoclasts usually lie directly against the bone matrix on endosteum, periosteum, and Haversian system bone surfaces, but unlike osteocytes, and presumably osteoblasts, they can move from one site of bone resorption to another. Osteoclasts appear to form by fusion of multiple bone-marrow-derived mononuclear cells. The osteoclast adheres to bone via binding of Arg-Gly-Asp (RGD)-containing peptides (green triangle) to the integrin αvβ3, membrane extension called the sealing zone; creates an isolated area between the bone and a portion of the osteoclast. Resorption is initiated by Carbonic anhydrase II enzyme that generates H + and HCO3 − ions; H+ is transported into the resorption pit by H+ATPase proton pump located in the ruffled border. HCO3 − ions are exchanged for Cl − by Cl − /HCO3 − exchanger at the non-resorptive surface. Chloride channels (ClC-7) located in the ruffled membrane pump the Cl− into the resorptive pit. This initiating signal that lead to insertion into the plasma membrane of lysosomal vesicles that contain cathepsin K. Cathepsin K is one of 11 lysosomal cysteine proteases (cathepsins) expressed in the human genome. Cathepsin K is located intracellularly in lysosomes and extracellularly in bone resorption lacunae. Demineralized organic bone matrix including type 1 collagen is degraded by cathepsin K, an acid protease and MMP-9 (matrix metalloproteinase 9) secreted into the resorptive pit One of the most distinctive features of osteoclasts is the complex folding of their cytoplasmic membrane where it lies against the bone matrix at sites of bone resorption. Consequently, the cells generate a Resorption pit at ruffled border (villus-like projections toward the bone) above the resorption lacuna, The ruffled or brushed border appears to play a critical role in bone resorption, possibly by increasing the surface area of the cell relative to the bone and creating a sharply localized environment that rapidly degrades bone matrix. The fluid between the brush border and the bone matrix probably has a high concentration of a. hydrogen ions (Several acids, including hydrochloric acid, citric acid and lactic acid, (they acidify the area to approximately pH 4.0) released from the mitochondria and secretory vesicles) cause dissolution of the bone salts. b. cathepsin K, an acid protease and MMP-9 which digest or dissolve the organic matrix of the bone, and the acids cause dissolution of the bone salts). In cancellous bone, osteoclasts resorbing the bone surface create a characteristic depression called a Howship's lacuna. Solubilized mineral components are released when the cell migrates; organic degradation products are partially released similarly and partially transcytosed to the basolateral surface for release When they have finished their bone resorbing activity, they may divide to reform multiple mononuclear cells. Osteoclasts usually exist in small but concentrated masses, and once a mass of osteoclasts begins to develop, it usually eats away at the bone for about 3 weeks, creating a tunnel that ranges in diameter from 0.2 to 1 millimeter and is several millimeters long. At the end of this time, the osteoclasts disappear, and the tunnel is invaded by osteoblasts instead; then new bone begins to develop. Bone deposition continues for several months, with the new bone being laid down in successive layers of concentric circles (lamellae) on the inner surfaces of the cavity until the tunnel is filled. Deposition of new bone ceases when the bone begins to encroach ‫اخترر‬on the blood vessels supplying the area. The canal through which these vessels run, called the haversian canal, is all that remains of the original cavity. Each new area of bone deposited in this way is called an osteon. Throughout life, bone is being constantly resorbed and new bone is being formed. The calcium in bone turns over at a rate of 100% per year in infants and 18% per year in adults. Mechanism of Bone deposition. First step: osteoid formation Osteoid is the un-mineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue. Osteoid makes up about 50% of bone volume and 40% of bone weight. Osteoblasts begin the process of forming bone tissue by secreting the osteoid as several specific proteins. When the osteoid becomes mineralized, it and the adjacent bone cells have developed into new bone tissue. As the osteoid is formed, some of the osteoblasts become entrapped in the osteoid and become quiescent‫ خامل‬. At this stage they are called osteocytes. Osteoid is composed of A. collagen molecules (called collagen monomers) B. ground substance: The ground substance is mostly made up of chondroitin and osteocalcin. Second step: mineral precipitation (mineralization) and bone hardening Mineralization is process by which minerals are deposited in the organic matrix, which is capable to accepting minerals Mineralization most important step in the formation of hard tissue Mineral content of the hard tissue is calcium hydroxyapatite crystal Process of mineralization occurs by aggregation of ions to form crystal Nucleation: The presence of nucleating substance allows crystal formation to occur, in absence of a locally increased ionic concentration Nucleation is of two types; 1) Homogenous nucleation: local increase in concentration of minerals  allows the formation of sufficient ionic crystal required for mineralization. 2) Heterogenous nucleation: presence of nucleating substance  allows crystal formation to occur, in absence of locally increased ionic concentration  The initial calcium salts to be deposited are not hydroxyapatite crystals but amorphous compounds (non crystalline), a mixture of salts such as CaHPO4 × 2H2O, Ca3 (PO4)2 × 3H2O, and others.  Then, by a process of substitution and addition of atoms, or reabsorption and re-precipitation, these salts are converted into the hydroxyapatite crystals over a period of weeks or months. A few percent may remain permanently in the amorphous ‫غير متبلور‬form, which is important because these amorphous salts can be absorbed rapidly when there is a need for extra calcium in the extracellular fluid. When deposition is initiated, the crux ‫الجوهر‬is then to: Control spontaneous precipitation from tissue fluids Limit it to well defined sites Factors inhibiting Mineralization: Mg2+ , Pyrophosphates , Nucleotides, Citrates Factors promoting Mineralization: Alkaline phosphatase, Nucleating substance (crystal poison) Theories of Mineralization: 1. Booster‫ تعزيز او تنشيط‬theory or Robinson’s alkaline phosphatase theory of mineralization Alkaline phosphatase present in the organic matrix can hydrolyze organic phosphates such as pyrophosphates  Release inorganic orthophosphate  local increase in phosphate ion concentration (Increase in local ion concentration has a boosting effect which would proportionately increase the proportion of phosphate ions to cause spontaneous precipitation)  spontaneous precipitation  Phosphate ions combine with the calcium ions available in tissue fluid to form unstable amorphous calcium phosphate  hydroxyapatite crystals. Not: Alkaline phosphatase may be playing an important role in mineralization by hydrolyzing pyrophosphate a. because pyrophosphate prevents mineralization therefore prevents crystal growth b. NOT because pyrophosphate is source of inorganic phosphate The basis of Alkaline phosphatase theory: Calcifying cartilage contains more alkaline phosphatase than non-calcifying cartilage. Slices of cartilage + incubated with calcium & organic phosphates= hydroxyapatite crystals were formed. Booster theory is least acceptable theory: Alkaline phosphatase is observed in other tissues which do not calcify. Inhibitors of certain enzymes which do not inhibit alkaline phosphatase activity are found to be preventing mineralization. Studies have shown that presence of inorganic phosphate and calcium is not sufficient to induce mineralization, because a. It requires action of some other enzymes other than alkaline phosphatase b. Initial cluster of crystal forms lattice, which is unstable. So, enough number of crystals doesn’t remain for the development of critical number of crystals c. Formation of cluster of ion crystal expenditure of energy is required. So, energy barrier must be overcome 2. Collagen seeding ‫ بذاا‬theory or nucleation theory or collagen template theory of mineralization: Collagen can act as template on mould upon which crystals can be laid down. Collagen acts as a nucleating substance reducing energy required for mineralization and allows crystal formation to occur even in absence of locally increase ionic concentration Apatite crystals deposited in the surface, holes & pores of collagen. Within a few days after the osteoid is formed, calcium salts begin to precipitate on the surfaces of the collagen fibers. The precipitates first appear at intervals along each collagen fiber, forming minute nidi ‫بؤرر‬ (single: nidus; the point of origin or focus) that rapidly multiply and grow over a period of days and weeks into the finished product, hydroxyapatite crystals. Objections: I. Fail to explain mineralization in enamel & cartilage II. Fails to explain mineralization in soft tissues though it contains collagen 3. Matrix vesicle theory of mineralization (most acceptable theory of mineralization) Matrix vesicle a small membrane bound structure lying free in the matrix Matrix vesicles are membrane-invested vesicles of 50– 200 nm in diameter, buds off from osteoblasts, chondrocytes and odontoblasts Matrix vesicles exist only in relation to initial mineralization Matrix vesicles form as an independent unit within the first form organic matrix. Matrix vesicles are sites for Ca and Pi accumulation by deposition of initial mineral complex (i.e. nucleation) occurs & hydroxyapatite is produced. Mineralization takes place in two distinct processes. Hypertrophic chondrocytes, osteoblasts, and odontoblasts bud matrix vesicles when mineralization begins. The mineralization process occurs within the matrix vesicles, in which hydroxyapatite {Ca10 (PO4)6(OH)2} crystals are formed. a. Phosphate (Pi) is derived from ‫كيف نسيطر على تركيز الفوسيت داخل الفسكل‬ 1. Membrane phospholipids, which are hydrolyzed by phospholipase C (PLC) to produce phosphocholine (PCho) and phosphoethanolamine (PEA). These phosphor-compounds are hydrolyzed by PHOSPO1: phosphoethanolamine/phosphocholine phosphatase, a cytosolic phosphatase that is abundant in the matrix vesicles, to yield inorganic phosphate (Pi). 2. Another source of Pi in the matrix vesicles is Pi that is transported through the Na/Pi cotransporter Pit1 that is also abundant on the matrix vesicle membrane. b. Calcium is incorporated into the matrix vesicles through annexin Ca2+ channels Developing hydroxyapatite crystals then penetrate the matrix vesicle membrane elongated in the extracellular space  deposit in the spaces between collagen fibrils to complete extracellular matrix mineralization. The concentration ratio of inorganic phosphate (Pi) to inorganic pyrophosphate (PPi) in the extracellular matrix is crucial in the mineralization because PPi is an inhibitor of hydroxyapatite formation. Two mechanisms are used for inorganic pyrophosphate (PPi) formation (decrease hydroxyapatite crystals). 1. Inorganic pyrophosphate (PPi) is formed in the extracellular matrix from ATP by the matrix vesicle membrane enzyme ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1) 2. Inorganic pyrophosphate (PPi) is also provided through the inorganic pyrophosphate transporter ankylosis protein human (ANKH) from the cytoplasm, in which inorganic pyrophosphate (PPi) is routinely formed by cellular metabolism. ankylosis protein human (ANKH) is distributed on the plasma membrane of hypertrophic chondrocytes and osteoblasts. Tissue non-specific-alkalin-ephosphatase (TNAP) on the membrane of the matrix vesicles hydrolyzes inorganic pyrophosphate (PPi) and yields inorganic phosphate (Pi), thereby reducing the levels of the PPi and promoting hydroxyapatite formation (increase hydroxyapatite crystals) ) hydroxyapatite crystals(‫ ) يعني نقصان ال‬inorganic pyrophosphate (PPi) ‫زيادة‬ ) hydroxyapatite crystals( ‫ ) يعني زيادة ال‬inorganic phosphate (Pi) ‫زيادة‬ This balance between the activities of TNAP, NPP1, and ANKH is crucial for the mineralization. Deficiencies of Nucleotide Pyrophosphatase Phosphodiesterase 1 (NPP1) or ANKylosis protein Human (ANKH) cause decreased extracellular Inorganic pyrophosphate (PPi) and excessive calcification of bone, such as bone spurs, or even calcification of other tissues such as tendons and ligaments of the spine, which occurs in people with a form of arthritis called ankylosing spondylitis. Precipitation of calcium in non-osseous tissues under abnormal conditions Hydroxyapatite crystals fail to precipitate in normal tissues except in bone despite the state of super- saturation of the ions, because inhibitors are present in almost all tissues of the body, as well as in plasma, to prevent such precipitation; such inhibitor are pyrophosphate, Matrix Gla protein (MGP), Osteopontin (OPN) and Fetain Unstable-initial cluster of ions needed to form a lattice structure the formation of clusters of ions requires the expenditure of energy and an energy barrier must be overcome for crystallization. For instance,  They precipitate in arterial walls in arteriosclerosis and cause the arteries to become bonelike tubes.  Calcium salts frequently deposit in degenerating tissues (as old fibrous TB) or in old blood clots. Value of Continual Bone Remodeling. The continual deposition and resorption of bone have several physiologically important functions. First, bone ordinarily adjusts its strength in proportion to the degree of bone stress. Consequently, bones thicken when subjected to heavy loads.  Bone stress determines osteoblastic deposition and calcification of bone Bone is deposited in proportion to the compressional load that the bone must carry. For instance, the bones of athletes become considerably heavier than those of non-athletes. if a person has one leg in a cast but continues to walk on the opposite leg, the bone of the leg in the cast becomes thin and as much as 30 percent remains thick and normally calcified. Therefore, continual physical stress stimulates osteoblastic deposition and calcification of bone. Bone stress determines the shape of bones under certain circumstances. For instance, if a long bone of the leg breaks in its center and then heals at an angle, the compression stress on the inside of the angle causes increased deposition of bone. Increased resorption occurs on the outer side of the angle where the bone is not compressed. After many years of increased deposition on the inner side of the angulated bone and resorption on the outer side, the bone can become almost straight, especially in children because of the rapid remodeling of bone at younger ages. ‫سقوط الكبار يؤدي الى كسور بسبب هشاشة العضام لقلة سرعة اسبدال العضام القديمة‬ Second, even the shape of the bone can be rearranged for proper support of mechanical forces by deposition and resorption of bone in accordance with stress patterns. Third, because old bone becomes relatively brittle ‫هر‬and weak, new organic matrix is needed as the old organic matrix degenerates. In this manner, the normal toughness of bone is maintained. Indeed, the bones of children, in whom the rates of deposition and absorption are rapid, show little brittleness in comparison with the bones of the elderly, in whom the rates of deposition and resorption are slow.