What Chemical Makes Bones Soft and Bendable Then Making Them Hard Again

Key Messages

• The bony skeleton is a remarkable organ that serves both a structural office, providing mobility, support, and protection for the torso, and a reservoir function, every bit the storehouse for essential minerals.

• During childhood and adolescence basic are sculpted by a process called modeling, which allows for the germination of new os at i site and the removal of old bone from another site inside the same bone. This procedure allows individual bones to grow in size and to shift in space.

• Much of the cellular activity in a bone consists of removal and replacement at the same site, a process called remodeling. The remodeling process occurs throughout life and becomes dominant by the time that bone reaches its pinnacle mass (typically by the early 20s). Remodeling continues throughout life so that most of the adult skeleton is replaced virtually every ten years.

• Both genes and the environment contribute to os wellness. Some elements of bone health are determined largely past genes, and errors in signaling by these genes can upshot in birth defects. External factors, such as diet and physical activity, are critically important to bone wellness throughout life, and these factors can be modified.

• The growth of the skeleton, its response to mechanical forces, and its part as a mineral storehouse are all dependent on the proper performance of a number of systemic or circulating hormones that reply to changes in blood calcium and phosphorus. If calcium or phosphorus are in brusque supply, the regulating hormones take them out of the bone to serve vital functions in other systems of the torso. Too many withdrawals can weaken the bone.

• Many things tin can interfere with the evolution of a potent and good for you skeleton. Genetic abnormalities can produce weak, thin basic, or bones that are too dense. Nutritional deficiencies can result in the germination of weak, poorly mineralized bone. Many hormonal disorders tin can also affect the skeleton. Lack of exercise, immobilization, and smoking tin besides take negative effects on os mass and force.

• Osteoporosis, the most mutual bone disease, typically does not manifest until tardily in life, when bone loss begins due to os breakup and decreased levels of bone formation. Loss of bone mass leads to the development of structural abnormalities that make the skeleton more frail.

The purpose of this chapter is to provide an overview of bone biology that volition help the reader to understand:

• why humans have basic;

• how bones work;

• how bones change during life;

• what keeps bones healthy;

• what causes bone disease, including the most mutual form, osteoporosis; and

• the future of bone biological science and what it means for preventing and treating bone affliction.

While dealing with a subject that is highly technical in nature, this affiliate attempts to explain bone biology in terms that a lay person tin can generally sympathise. It is intended to provide the reader with the background needed to empathize the basis for some of the preventive, diagnostic, and handling approaches related to os disease that are discussed in detail afterwards in this report. Those interested in a more detailed review of os biology and bone disease can consult any of a number of contempo texts (Bilezikian et al. 2001, Marcus et al. 2001, Favus 2003).

Why Practise We Accept Basic?

The bony skeleton is a remarkable organ that serves both a structural role—providing mobility, support, and protection for the torso—and a reservoir function, as the storehouse for essential minerals. It is non a static organ, merely is constantly changing to meliorate comport out its functions. The development of the bony skeleton likely began many eons ago, when animals left the calcium-rich ocean, first to live in fresh h2o where calcium was in short supply, and so on dry land where weight begetting put much greater stress on the skeleton. The architecture of the skeleton is remarkably adapted to provide acceptable strength and mobility and so that basic practice not intermission when subjected to substantial impact, fifty-fifty the loads placed on bone during vigorous physical activity. The shape or structure of os is at least equally of import as its mass in providing this forcefulness.

The skeleton is as well a storehouse for two minerals, calcium and phosphorus, that are essential for the functioning of other body systems, and this storehouse must be called upon in times of demand. The maintenance of a abiding level of calcium in the blood also every bit an adequate supply of calcium and phosphorus in cells is disquisitional for the office of all body organs, but particularly for the fretfulness and muscle. Therefore, a complex system of regulatory hormones has adult that helps to maintain adequate supplies of these minerals in a variety of situations. These hormones deed not but on bone merely on other tissues, such as the intestine and the kidney, to regulate the supply of these elements. Thus ane reason that bone health is difficult to maintain is that the skeleton is simultaneously serving 2 unlike functions that are in competition with each other. Showtime, bone must be responsive to changes in mechanical loading or weight begetting, both of which require potent bones that have aplenty supplies of calcium and phosphorus. When these elements are in short supply the regulating hormones take them out of the bone to serve vital functions in other systems of the body. Thus the skeleton tin can be likened to a bank where we can deposit calcium or phosphorus and then withdraw them afterward in times of need. Yet, too many withdrawals weaken the bone and can lead to the most common bone disorder, fractures.

Both the amount of bone and its architecture or shape are determined by the mechanical forces that act on the skeleton. Much of this is adamant genetically and so that each species, including humans, has a skeleton that is adapted to its functions. However, at that place can exist bully variation inside a species, so that some individuals will have strong bones and others will have weak bones, largely considering of differences in their genes (Huang et al. 2003). Moreover, bone mass and compages are further modified throughout life every bit these functions and the mechanical forces required to fulfill them modify. In other words, bones volition weaken if they are not subjected to adequate amounts of loading and weight bearing for sufficient periods of time. If they are non (such as in the weightless condition of infinite travel), rapid bone loss can occur. In other words, as with muscle, it is "utilise it or lose it" with bone likewise. Conversely, the amount and compages of the bones tin can exist improved by mechanical loading. However, as described in Chapter half dozen, some types of practice may exist better than others in strengthening the skeleton.

To reply to its dual roles of support and regulation of calcium and phosphorus, as well as to repair any impairment to the skeleton, bone is constantly changing. Erstwhile bone breaks downward and new os is formed on a continuous basis. In fact, the tissue of the skeleton is replaced many times during life. This requires an exquisitely controlled regulatory system that involves specialized cells that communicate with each other. These cells must respond to many different signals, both internal and external, mechanical and hormonal, and systemic (affecting the whole skeleton) and local (affecting simply a small region of the skeleton). Information technology is not surprising that with and so many different tasks to perform and so many unlike factors regulating how the skeleton grows, adapts, and responds to changing demands, there are many ways that these processes tin go astray.

How Bones Work

Bone is a composite fabric, consisting of crystals of mineral leap to protein. This provides both strength and resilience so that the skeleton can absorb touch without breaking. A construction made only of mineral would be more breakable and break more easily, while a construction made only of poly peptide would be soft and bend as well easily. The mineral phase of bone consists of small crystals containing calcium and phosphate, called hydroxyapatite. This mineral is bound in an orderly manner to a matrix that is fabricated up largely of a single protein, collagen. Collagen is made by bone cells and assembled as long thin rods containing three intertwined protein chains, which are so assembled into larger fibers that are strengthened by chemical connections between them. Other proteins in os can aid to strengthen the collagen matrix even further and to regulate its ability to bind mineral. Very small changes in the shape of the bone tin can act on the cells inside os (the osteocytes), which produce chemical signals that allow the skeleton to respond to changes in mechanical loading. Abnormalities in the collagen scaffold can occur equally a result of a genetic disorder called osteogenesis imperfecta, while the failure of mineral deposition can be the result of rickets and osteomalacia, conditions that upshot in marked weakening of the skeleton (see beneath and Chapter three).

To provide the body with a frame that is both light and stiff, basic are hollow. The outer dense shell is called cortical os, which makes up roughly three-quarters of the total skeletal mass. Within the cortical shell is a fine network of connecting plates and rods called trabecular bone that makes upwards the remaining 25 pct (Effigy 2-ane). Most bones are hollow structures in which the outer cortical bone shell defines the shape of the bone. This cortical beat is essential considering information technology provides strength, sites for firm attachment of the tendons, and muscles and protection without excessive weight. The inner trabecular network has two important functions. Information technology provides a large bone surface for mineral exchange. In add-on, trabecular bone helps to maintain skeletal strength and integrity, as information technology is particularly abundant in the spine and at the ends of the long bones, sites that are under continuous stress from motion and weight-bearing. Fractures are common at these sites when the os is weakened (Kontulainen, Sievanen et al. 2003). The rods and plates of trabecular bone are aligned in a blueprint that provides maximal strength without too much majority, much in the way that architects and engineers design buildings and bridges. The shape and size of both cortical and trabecular os tin can respond to different kinds of stress produced past physical activity. For example, in almost people the cortex of their dominant arm is larger than that of their non-ascendant arm. The difference in cortex size is fifty-fifty larger for tennis players and other athletes who routinely use a dominant arm in their sporting activities. Basic do not work in isolation, but rather are part of the musculoskeletal system, providing the "lever" that allows muscles to movement (by pulling on the lever). Thus muscle activity is important for the normal part of the bone. When the mechanical forcefulness produced by muscle is lost—for example, in patients with muscular dystrophy or paralysis—bone mass and strength are also rapidly lost. Many bones in the skeleton likewise take connecting joints that provide greater flexibility of move. These joints are sites of great mechanical stress and are subject to injury and to degeneration with aging. The most mutual type of joint degeneration is osteoarthritis, a painful, degenerative condition that affects the hip, knees, cervix, lower back, and/or small joints of the paw. These joint diseases consequence from very different causes and require very dissimilar management than do os diseases, and consequently they are not covered in this report. Still it is important to recognize that the basic, joints, and muscles are the key parts of an integrated "musculoskeletal system." Problems with any one component of this system tin affect the other components. Thus, weakness of the muscles can lead to loss of bone and articulation damage, while degeneration of the joints leads to changes in the underlying bone, such as the bony spurs or protuberances that occur in osteoarthritis.

Figure 2-ane

Frontal Longitudinal Midsection of Upper Femur. Source: Gray 1918.

How Bones Change Throughout Life

Throughout life, bones modify in size, shape, and position. Two processes guide these changes—modeling and remodeling. When a os is formed at 1 site and broken down in a different site its shape and position is changed. This is chosen modeling (Figure ii-ii). However, much of the cellular activity in a bone consists of removal and replacement at the same site, a process called remodeling. The residual of this section explains why and how these processes occur.

Figure ii-ii

Modeling and Remodeling. Note: In modeling, osteoblast and osteoclast activeness are not linked and rapid changes can occur in the amount, shape, and position of bone. In remodeling, osteoblast action is coupled to prior osteoclast action. Net changes in (more...)

Why Nosotros Need Modeling and Remodeling

During babyhood and boyhood bones are sculpted by modeling, which allows for the formation of new bone at ane site and the removal of old bone from some other site inside the same os (Seeman 2003) (Effigy 2-two). This procedure allows individual bones to abound in size and to shift in space. During childhood bones grow because resorption occurs within the bone while formation of new bone occurs on its outer (periosteal) surface. At puberty the bones become thicker because formation tin can occur on both the outer and inner (endosteal) surfaces. Equally people get older, resorption occurs on inner surfaces while germination occurs on outer surfaces, which can partially compensate for the loss of strength due to the thinning of the cortex. The size and shape of the skeleton follows a genetic program, just can be greatly affected by the loading or affect that occurs with physical action. Ultimately bones accomplish a shape and size that fits best to their function. In other words, "class follows function."

The remodeling process occurs throughout life and becomes the dominant procedure by the fourth dimension that bone reaches its summit mass (typically by the early on 20s). In remodeling, a pocket-sized amount of bone on the surface of trabeculae or in the interior of the cortex is removed and and so replaced at the same site (Figure 2-2). The remodeling process does non change the shape of the bone, simply it is nevertheless vital for bone health, for a variety of reasons. Start, remodeling repairs the damage to the skeleton that can event from repeated stresses by replacing pocket-sized cracks or deformities in areas of cell harm. Remodeling also prevents the aggregating of too much erstwhile bone, which can lose its resilience and become brittle. Remodeling is too of import for the function of the skeleton as the bank for calcium and phosphorus. Resorption (the process of breaking downwards bone), especially on the surface of trabecular os, tin supply needed calcium and phosphorus when there is a deficiency in the diet or for the needs of the fetus during pregnancy or an infant during lactation. When calcium and phosphorus supplies are aplenty the formation phase of remodeling can accept upwardly these minerals and furnish the bank.

Modeling and remodeling go along throughout life and then that most of the adult skeleton is replaced about every 10 years. While remodeling predominates by early adulthood, modeling tin still occur particularly in response to weakening of the bone. Thus with aging, if excessive amounts of os are removed from the inside, some new bone can be laid down on the outside, thus preserving the mechanical strength of the bone despite the loss of bone mass.

How Modeling and Remodeling Occur

The process of building the skeleton and continuously reshaping it to respond to internal and external signals is carried out by specialized cells that can be activated to grade or suspension downwards bone. Both modeling and remodeling involve the cells that course bone called osteoblasts and the cells that intermission downwards bone, called osteoclasts (Figure 2-iii). In remodeling there is an important local interaction betwixt osteoblasts or their precursors (the cells that will develop into osteoblasts by acquiring more specialized functions—a process chosen differentiation) and osteoclasts or their precursors. Since remodeling is the main style that bone changes in adults and abnormalities in remodeling are the primary cause of bone disease, it is critically important to empathize this procedure. In addition, contempo research has provided exciting data about these prison cell interactions.

Effigy 2-3

Bone Remodeling. Notation: The sequence of activation, resorption, reversal, and formation is illustrated hither. The activation stride depends on cells of the osteoblast lineage, either on the surface of the bone or in the marrow, acting on blood cell precursors (more than...)

Osteoblasts are derived from forerunner cells that tin can too be stimulated to go muscle, fatty or cartilage; however, under the right conditions these cells change (or differentiate) to course new bone, producing the collagen that forms the scaffolding or os matrix. This calcium- and phosphate-rich mineral is added to the matrix to form the hard, nevertheless resilient, tissue that is salubrious os. Osteoblasts lay downwardly os in orderly layers that add forcefulness to the matrix. Some of the osteoblasts are buried in the matrix as it is being produced and these are now called osteocytes. Others remain as thin cells that cover the surface and are called lining cells. Osteocytes are the about numerous cells in os and are extensively connected to each other and to the surface of osteoblasts by a network of small sparse extensions. This network is critical for the ability of bone to reply to mechanical forces and injury. When the skeleton is subjected to touch on there is fluid movement around the osteocytes and the long-cell extensions that provides signals to the bone cells on the surface to modify their activeness, either in terms of changes in bone resorption or formation. Failure of the osteoblasts to brand a normal matrix occurs in a congenital disorder of the collagen molecule called osteogenesis imperfecta. Inadequate bone matrix formation also occurs in osteoporosis, specially in the form of osteoporosis produced past an excess of the adrenal hormones called glucocorticoid-induced osteoporosis. This form of osteoporosis differs from primary osteoporosis and most other forms of secondary osteoporosis considering with glucocorticoid-induced osteoporosis inhibition of os formation is the dominant mechanism for weakening of the skeleton.

The osteoclasts remove bone past dissolving the mineral and breaking down the matrix in a process that is called bone resorption. The osteoclasts come from the same precursor cells in the os marrow that produce white blood cells. These precursor cells tin can also circulate in the claret and exist bachelor at unlike sites in demand of bone breakdown. Osteoclasts are formed by fusion of small forerunner cells into large, highly active cells with many nuclei. These large cells tin fasten onto the os, seal off an area on the surface, and develop a region of intense action in which the cell surface is highly irregular, called a ruffled border. This ruffled border contains transport molecules that transfer hydrogen ions from the cells to the bone surface where they tin dissolve the mineral. In addition, packets of enzymes are secreted from the ruffled edge that can break down the matrix. Excessive os breakdown by osteoclasts is an important crusade of bone fragility non only in osteoporosis, only as well in other bone diseases such as hyperparathyroidism, Paget's affliction, and fibrous dysplasia (see Chapter 3). Inhibitors of osteoclastic bone breakdown take been developed to treat these disorders (see Chapter 9).

Removal and replacement of bone in the remodeling bike occurs in a carefully orchestrated sequence that involves communication betwixt cells of the osteoblast and osteoclast lineages (Hauge, Qvesel et al. 2001; Parfitt 2001). It is controlled by local and systemic factors that regulate os remodeling to fulfill both its structural and metabolic functions. The activation of this process involves an interaction between cells of the osteoblastic lineage and the precursors that will become osteoclasts. What stops this process is not known, but the osteoclasts machinery clearly slows down and the osteoclasts die by a process that is called programmed cell death. Thus the corporeality of bone removed can be controlled by altering the rate of production of new osteoclasts, blocking their activity, or altering their life span. Most current treatments for osteoporosis piece of work by slowing down osteoclastic bone breakdown through apply of antiresorptive agents.

The activation and resorption phases are followed by a brief reversal stage (Everts, Delaisse et al. 2002). During the reversal phase the resorbed surface is prepared for the subsequent germination phase, in part by producing a sparse layer of poly peptide, rich in sugars, which is chosen the cement line and helps class a strong bond between the old bone and the newly formed bone.

These three phases are relatively rapid, probably lasting only 2 to 3 weeks in humans. The terminal phase of bone formation takes much longer, lasting up to 3 or iv months. Thus active remodeling at many sites tin weaken the bone for a considerable period of fourth dimension (fifty-fifty if formation catches up eventually), every bit many defects class in the bony structure that have not withal been filled. Formation is carried out by large active osteoblasts that lay down successive layers of matrix in an orderly mode that provides added force. The addition of minerals to the collagenous matrix completes the process of making strong bone. Any error in this complex process can lead to bone illness.

Since remodeling serves both the structural and metabolic functions of the skeleton, it tin can be stimulated both past the hormones that regulate mineral metabolism and past mechanical loads and local harm acting through local factors. Repair of local harm is an important function of remodeling. Over time repeated small stresses on the skeleton tin can produce areas of defective os, termed micro-damage. Replacement of that damaged os by remodeling restores bone forcefulness. Signals for these responses are probably developed by the network of osteocytes and osteoblasts, which, through their multiple connections, tin can find changes in the stress placed upon bone and in the health of the small-scale areas of micro-damage. Factors that bear upon the formation, activity, and life span of osteoclasts and osteoblasts as they develop from forerunner cells can impact the remodeling cycle. Drugs take been developed that act in these ways, with the goal of reducing bone loss or increasing bone germination and maintaining skeletal health.

What Keeps Basic Healthy?

Both genes and the environment contribute to bone wellness. Some elements of bone health (east.one thousand., the size and shape of the skeleton) are determined largely by genes, and errors in signaling by these genes tin can result in birth defects. External factors, such every bit diet and physical action, are critically important to bone health throughout life and can be modified. Equally noted above, the mechanical loading of the skeleton is essential for maintenance of normal bone mass and architecture. In addition, the skeleton needs certain nutritional elements to build tissue. Non simply does the skeleton require the same nutritional elements every bit the rest of the body, but information technology also has a special requirement for large amounts of calcium and phosphorus. While adequate levels of these minerals can exist obtained from the female parent during pregnancy and nursing, they must come from the nutrition thereafter.

The growth of the skeleton, its response to mechanical forces, and its role as a mineral storehouse are all dependent on the proper functioning of a number of systemic or circulating hormones produced outside the skeleton that piece of work in concert with local regulatory factors. The systemic hormones that affect the supply of calcium and phosphorus and the formation and breakup of bone are listed in Tabular array 2-i. This complex organisation of regulatory hormones responds to changes in blood calcium and phosphorus, acting not simply on os but likewise on other tissues such as the intestine and the kidney. The system is illustrated for calcium regulation in Figure 2-4. Under normal atmospheric condition only part of the dietary calcium is captivated and some calcium is secreted into the abdominal tract then that the cyberspace amount of calcium inbound the body ordinarily is only a minor proportion of dietary calcium. In healthy young adults there is calcium balance, where the amount taken in is equal to the corporeality excreted. The basic are constantly remodeling, simply breakup and formation are equal. The kidney filters the blood, including a big amount of calcium, but most of this is taken back into the trunk past the kidney cells. When calcium and/or phosphorus are in short supply, the regulating hormones take them out of the bone to serve vital functions in other systems of the body. Too many withdrawals can weaken the os. The regulatory hormones too play critical roles in determining how much bone is formed at different phases of skeletal growth and how well bone force and mass is maintained throughout life. For case, sex hormones and the growth hormone system described below are increased during puberty, a time of speedily increased skeletal growth. Finally, it is important to recall that the effects of hormones and mechanical forces on the skeleton are closely linked. For instance, the ability of bone to respond to mechanical loading is impaired in animals lacking the receptor for estrogen (Lee et al. 2003).

Table two-one

About Critical Systemic Hormones Regulating Bone.

Effigy 2-4

Regulation of the Calcium Levels in the Body Fluids. Note: The extracellular fluid (ECF) calcium level is regulated non only by bone, but besides by the intestine and kidney every bit shown in this figure. In addition to the limited absorption of calcium from the (more...)

Genes, hormones, local factors, and lifestyle all play a function in determining one's pinnacle bone mass, a level that is typically achieved past the time an individual reaches his or her late teens or early on 20s. The stronger the basic are at this time, the ameliorate able they are to deal with whatever withdrawals of calcium and phosphorus that are needed and with whatsoever other changes to os that occur with aging.

What follows is a brief description of the most important regulating hormones with respect to bone wellness.

Calcium-Regulating Hormones

Iii calcium-regulating hormones play an important part in producing healthy bone: 1) parathyroid hormone or PTH, which maintains the level of calcium and stimulates both resorption and formation of bone; 2) calcitriol, the hormone derived from vitamin D, which stimulates the intestines to absorb enough calcium and phosphorus and also affects bone direct; and 3) calcitonin, which inhibits bone breakdown and may protect against excessively high levels of calcium in the claret.

Parathyroid hormone or PTH

PTH is produced by four small glands adjacent to the thyroid gland. These glands precisely control the level of calcium in the blood. They are sensitive to modest changes in calcium concentration and then that when calcium concentration decreases even slightly the secretion of PTH increases. PTH acts on the kidney to conserve calcium and to stimulate calcitriol product, which increases abdominal absorption of calcium. PTH as well acts on the bone to increase move of calcium from bone to blood. Excessive production of PTH, commonly due to a small tumor of the parathyroid glands, is called hyperparathyroidism and can lead to os loss. PTH stimulates bone germination too as resorption. When small amounts are injected intermittently, os formation predominates and the bones go stronger (Rubin, Cosman et al. 2002). This is the basis for a new handling for osteoporosis (see Chapter 9).

In contempo years a second hormone related to PTH was identified called parathyroid hormone-related poly peptide (PTHrP). This hormone normally regulates cartilage and os development in the fetus, only it tin can be over-produced past individuals who accept certain types of cancer. PTHrP then acts similar PTH, causing excessive bone breakdown and abnormally high claret calcium levels, called hypercalcemia of malignancy (Stewart 2002).

Calcitriol

Calcitriol is the hormone produced from vitamin D (Norman, Okamura et al. 2002). Calcitriol, too chosen ane,25 dihydroxy vitamin D, is formed from vitamin D by enzymes in the liver and kidney. Calcitriol acts on many different tissues, but its near important action is to increase intestinal absorption of calcium and phosphorus, thus supplying minerals for the skeleton. Vitamin D should not technically be chosen a vitamin, since it is non an essential food chemical element and can be made in the peel through the activity of ultra violet light from the sun on cholesterol. Many people need vitamin D in their diet because they exercise not derive adequate levels from exposure to the lord's day. This need occurred as people began to live indoors, wear dress, and movement further n. In northern latitudes the sun'south rays are filtered in the winter and thus are not potent plenty to make sufficient vitamin D in the pare. Vitamin D deficiency leads to a disease of lacking mineralization, chosen rickets in children and osteomalacia in adults. These conditions can effect in os hurting, bowing and deformities of the legs, and fractures. Handling with vitamin D can restore calcium supplies and reduce bone loss.

Calcitonin

Calcitonin is a third calcium-regulating hormone produced by cells of the thyroid gland, although past different cells than those that produce thyroid hormones (Sexton, Findlay et al. 1999). Calcitonin can block os breakdown past inactivating osteoclasts, but this effect may be relatively transient in adult humans. Calcitonin may be more important for maintaining os development and normal blood calcium levels in early life. Excesses or deficiencies of calcitonin in adults exercise not cause problems in maintaining blood calcium concentration or the strength of the os. However, calcitonin can exist used as a drug for treating bone disease.

Sex Hormones

Along with calcium-regulating hormones, sex hormones are likewise extremely important in regulating the growth of the skeleton and maintaining the mass and strength of os. The female hormone estrogen and the male hormone testosterone both have effects on bone in men and women (Falahati-Nini, Riggs et al. 2000). The estrogen produced in children and early on in puberty can increase bone growth. The high concentration that occurs at the end of puberty has a special effect—that is, to terminate further growth in height by endmost the cartilage plates at the ends of long bone that previously had allowed the basic to abound in length.

Estrogen acts on both osteoclasts and osteoblasts to inhibit os breakdown at all stages in life. Estrogen may also stimulate bone formation. The marked decrease in estrogen at menopause is associated with rapid bone loss. Hormone therapy was widely used to preclude this, but this practice is now controversial because of the risks of increased chest cancer, strokes, blood clots, and cardiovascular disease with hormone therapy (see Chapter 9).

Testosterone is of import for skeletal growth both because of its direct furnishings on os and its ability to stimulate muscle growth, which puts greater stress on the os and thus increases os formation. Testosterone is also a source of estrogen in the torso; it is converted into estrogen in fat cells. This estrogen is important for the basic of men as well as women. In fact, older men accept college levels of circulating estrogen than do postmenopausal women.

Other Important Hormones

Growth hormone from the pituitary gland is also an of import regulator of skeletal growth. It acts past stimulating the production of another hormone called insulin-similar growth factor-i (IGF-i), which is produced in large amounts in the liver and released into circulation. IGF-one is also produced locally in other tissues, particularly in bone, also under the control of growth hormone. The growth hormone may also directly affect the os—that is, not through IGF-i (Wang et al. 2004). Growth hormone is essential for growth and it accelerates skeletal growth at puberty. Decreased product of growth hormone and IGF-1 with historic period may be responsible for the disability of older individuals to form bone rapidly or to supplant bone lost by resorption (Yakar and Rosen 2003). The growth hormone/IGF-one organization stimulates both the bone-resorbing and bone-forming cells, but the dominant upshot is on os germination, thus resulting in an increase in bone mass.

Thyroid hormones increment the energy production of all trunk cells, including bone cells. They increase the rates of both bone formation and resorption. Deficiency of thyroid hormone can impair growth in children, while excessive amounts of thyroid hormone can cause likewise much os breakup and weaken the skeleton (Vestergaard and Mosekilde 2002). The pituitary hormone that controls the thyroid gland, thyrotropin or TSH, may too accept direct furnishings on os (Abe et al. 2003).

Cortisol, the major hormone of the adrenal gland, is a critical regulator of metabolism and is important to the body's power to respond to stress and injury. Information technology has complex furnishings on the skeleton (Canalis and Delany 2002). Small amounts are necessary for normal os evolution, simply large amounts block bone growth. Synthetic forms of cortisol, called glucocorticoids, are used to treat many diseases such as asthma and arthritis. They can cause bone loss due both to decreased os formation and to increased bone breakdown, both of which lead to a high hazard of fracture (Kanis et al. 2004).

There are other circulating hormones that touch on the skeleton as well. Insulin is important for bone growth, and the response to other factors that stimulate os growth is impaired in individuals with insulin deficiency (Lu et al. 2003, Suzuki et al. 2003). A recently discovered hormone from fatty cells, leptin, has too been shown to have effects on os (Elefteriou et al. 2004, Cornish et al. 2002).

What Causes Diseases of Bone?

Maintaining a potent and healthy skeleton is a complicated procedure that requires having the right amount of bone with the right structure and composition in the right identify. At that place are many things that can go wrong along the way.

Genetic abnormalities can produce weak, sparse basic, or bones that are too dense. The disease osteogenesis imperfecta is caused by abnormalities in the collagen molecule that make the matrix weak and can pb to multiple fractures. In another congenital disorder, osteopetrosis, the bones are too dumbo because of failure of osteoclast formation or function. This failure of the remodeling process results in persistence of trabecular bone in the marrow space and so that the marrow cavity may not be large enough to form red and white blood cells normally. These dense bones cannot remodel well in response to mechanical forces or micro impairment and hence may be weaker and field of study to fracture even though bone mass is increased. At that place are besides other abnormalities of the genes that impact the size and shape of the skeleton and can cause deformities or abnormal growth.

Nutritional deficiencies, particularly of vitamin D, calcium, and phosphorus, tin issue in the formation of weak, poorly mineralized os. In children, vitamin D deficiency produces rickets in which there is not only a marked weakness of bone and fractures merely also bowing of the long basic and a characteristic deformity due to overgrowth of cartilage at the ends of the bones. In adults, vitamin D deficiency leads to a softening of the bone (a status known as osteomalacia) that tin too lead to fractures and deformities.

Many hormonal disorders tin as well bear on the skeleton. Overactive parathyroid glands or hyperparathyroidism can cause excessive bone breakdown and increase the risk of fractures. In severe cases, large holes or cystic lesions appear in the os, which makes them specially fragile. A deficiency of the growth hormone/IGF-1 system tin can inhibit growth, leading to short stature. Loss of gonadal part or hypogonadism in children and young adults can cause astringent osteoporosis due to loss of the effects of testosterone and estrogen. In improver, likewise much cortisol product by the adrenal gland can occur in Cushing's syndrome.

Employ of glucocorticoids as medication is a common cause of bone disease. Backlog glucocorticoids will terminate os growth in children and cause marked thinning of the bone in adults, often leading to fracture.

Many bone disorders are local, affecting only a small-scale region of the skeleton. Inflammation can lead to bone loss, probably through the production of local resorbing factors by the inflammatory white cells. This process can occur around the affected joints in patients with arthritis. Bacterial infections, such as severe mucilage inflammation or periodontal disease, can produce loss of the bones around the teeth, and osteomyelitis tin can produce a loss of bone at the site of infection. This type of bone loss is due to the straight damaging effect of bacterial products as well every bit the production of resorbing factors by white cells. Paget'due south illness is a multifaceted condition in which the first modify is the formation of big, highly active, and unregulated osteoclasts that produce aberrant os resorption. The precise cause of Paget'due south disease is not known, but it appears to be the result of both genetic factors and environmental factors, possibly a viral infection. The osteoblasts effort to repair this damage by increasing os formation. Still, the normal bone architecture has been disrupted, leading to weak basic and the potential for fractures and deformities (even though the bones may appear dense on an x-ray). One reason for this is that the new os formed is hell-raising, "woven" bone, which does non have the proper alignment of mineral crystals and collagen matrix. In addition, the new bone may not be in the right place to provide strength.

What Is Osteoporosis?

Osteoporosis is by far the nearly common bone affliction. Osteoporosis is "a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture" (Osteoporosis 2000). The composition of the mineral and matrix, the fine structure of the trabecular bone, the porosity of the cortical bone, and the presence of micro-fractures and other forms of damage in bone are all important in determining bone strength. Changes in the fine structure or micro-architecture of trabecular bone are peculiarly important since the most common fractures in osteoporosis occur at the spine, wrist, and hip, sites where trabecular os predominates. Equally shown in Effigy 2-v, the structure of normal trabecular bone consists of well-connected plates or broad bands that provide dandy strength. In individuals with osteoporosis these bands are disrupted and often go thin, weakened rods. Some of these rods are no longer connected to another slice of os, meaning that they no longer contribute to bone strength.

Figure two-5

Normal vs. Osteoporotic Bone. Note: These pictures, called scanning electron micrographs, are from biopsies of a normal and an osteoporotic patient. The normal bone shows a blueprint of stiff interconnected plates of bone. Much of this os is lost in (more...)

Unfortunately, however, it is non possible to measure bone strength direct, or to discover changes in the micro-architecture of bone in living patients. The mass of bone, its density, and its general shape can be determined by radiographs and absorptiometry (meet Chapter 8). These measures are used as "proxies" for bone strength in assessing the gamble of osteoporosis today.

There are a number of different means in which osteoporosis can develop, with the skeleton becoming more fragile and the risk of fracture increasing (Raisz and Rodan 2003). Some of the most of import mechanisms that lead to skeletal fragility and fractures are listed in Table two-2. Many people have relatively weak bones fifty-fifty as young adults because of their genes or considering of suboptimal nutrition and lifestyle. Yet, fractures due to bone fragility rather than severe injury are uncommon in young adults. Information technology is typically not until later in life that bone loss begins due to bone breakdown, a procedure that accelerates around the fourth dimension of menopause in women. At the same time, bone formation tends to subtract with age in both men and women, typically failing to keep upward with the rate of bone resorption. An imbalance between bone resorption and bone formation results in loss of bone mass, leading to the development of structural abnormalities that make the skeleton more fragile. At that place are a number of unlike combinations of increased resorption and decreased formation that can result in a weakened skeletal structure (see Figure 2-5). Each of these pathways can be involved in producing skeletal fragility at different times or sites within an individual patient. Since bone breakdown is the first step in this process, blocking os resorption is 1 way to decrease bone loss and prevent fractures. Information technology is currently the most widely used therapeutic approach in osteoporosis. Stimulation of os formation tin can also reverse skeletal fragility; new therapies based on this approach have recently been developed (Chapter nine).

Table two-2

Causes of Os Loss and Fractures in Osteoporosis.

The Time to come: Where a Meliorate Understanding of Os Biology Can Take United states

This brief overview of the basics of bone health and disease provides a framework for the discussion of what is known about the causes, prevention, and treatment of skeletal disorders today. Many knowledge gaps remain, and information technology is still unclear precisely why so many people endure fractures. Fortunately there have recently been a number of exciting new discoveries nearly skeletal regulation, and in that location are undoubtedly many more to come up. These discoveries will further increase our understanding of bone wellness and illness.

For example, contempo discoveries have shown how osteoblastic and osteoclastic cells communicate and provide signals to begin the process of resorption (Effigy 2-vi). The osteoblastic cells produce macrophage colony stimulating cistron (Thou-CSF) and receptor activator of nuclear gene kappa B ligand (RANKL) (Khosla 2001), proteins that demark to receptors on the osteoclast precursors, stimulate their proliferation and differentiation, and increase osteoclast activity. Osteoblastic cells as well produce a poly peptide called osteoprotegerin that can bind RANKL and forestall information technology from interacting with osteoclastic cells. The hormones and local factors that stimulate os resorption deed on this arrangement. The balance between RANKL and osteoprotegerin (OPG) production is probably critical in determining how fast os breaks down. RANKL in bone is increased in individuals with estrogen deficiency (Eghbali-Fatourechi et al. 2003). While RANKL excess or osteoprotegerin deficiency would be expected to cause os loss, measurements of the amounts of these proteins in circulating blood do non support this theory. OPG levels are higher and RANKL levels are lower in patients with fractures or depression bone mass (Schett et al. 2004, Jorgensen et al. 2004). On the other hand, OPG or drugs that act like it by interfering with the binding of RANKL could exist useful in the handling of osteoporosis.

Figure 2-6

How Osteoclasts Are Formed. Note: The interaction between cells of the osteoblastic lineage and the osteoclast lineage is illustrated here. The osteoblastic cells produce several proteins that regulate osteoblast germination and activeness. One is macrophage (more than...)

Recently another signaling organization was discovered in bone involving a receptor called lipoprotein receptor-related poly peptide 5. Patients with over-activity in this receptor have potent basic that typically do not fracture (Boyden, Mao et al. 2002; Little, Carulli et al. 2002). Patients in whom this receptor does not function grade astringent osteoporosis (Gong, Slee et al. 2001). Smaller variations in the gene for this receptor may have an important influence on bone size and strength (Ferrari et al. 2004). Many other genes have also recently been identified every bit influencing bone mass and strength. A cistron for an enzyme called lipoxygenase was recently found to affect bone mass in mice (Klein et al. 2004). Genetics studies in Republic of iceland accept shown that variants in one of the genes for bone morphogenetic proteins are associated with osteoporosis (Styrkarsdottir et al. 2003). There are also unidentified genes on specific sites on chromosomes that appear to control bone mass and architecture.

All of these new findings could ultimately lead to much better ways of determining whether or non an individual will develop a disorder of the skeleton. Plenty data exists today about the causes, prevention, diagnosis, and treatment of os diseases to increase the bone health and decrease the risk of fracture amidst Americans today. The goal of this report is to describe how this can be accomplished and how both personal and public health measures can promote bone health in our population.

Cardinal Questions for Future Research

Remarkable progress in furthering our understanding of the cellular, molecular biology, and genetics of skeletal tissues in the last quarter century has provided answers to many fundamental questions. Equally expected, these answers accept given rise to additional research questions, equally outlined below. The answers to these new questions should, in turn, lead to new approaches to diagnosis, prevention, and handling. Thus it is important to maintain stiff support for basic inquiry, even as existing inquiry findings are practical to the everyday practise of medicine.

• How does the normal skeleton answer to mechanical forces and maintain the best structure?

• How is this response lost in those individuals who develop bone affliction? Local factors that contribute to this process have been identified but their specific roles are not known. In improver, there is a general understanding of os remodeling, but there are many specific steps—in particular the reversal phase—nearly which piffling is known.

• How precisely does estrogen maintain bone mass and strength?

• What is the relative importance of other circulating hormones in maintaining bone health? These include not only the calcium and growth-regulating hormones, but also recently identified hormones such as leptin.

• How do newly identified genes and proteins (e.1000., the Wnt signaling pathway) that touch bone cells work?

References

1. Abe Due east, Marians RC, Yu West, Wu XB, Ando T, Li Y, Iqbal J, Eldeiry 50, Rajendren Chiliad, Blair HC, et al. TSH is a negative regulator of skeletal remodeling. Cell. 2003 Oct 17;115(ii):151–62. [PubMed: 14567913]

2. Bilezikian JP, Marcus R, Levine MA, editors. The parathyroids. 2nd ed. San Diego (CA): Bookish Printing; 2001.

3. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor-related poly peptide 5. North Engl J Med. 2002 May 16;346(20):1513–21. [PubMed: 12015390]

4. Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann Due north Y Acad Sci. 2002 Jun:966, 73–81. [PubMed: 12114261]

5. Cornish J, Callon KE, Bava U, Lin C, Naot D, Hill BL, Grey AB, Broom N, Myers DE, Nicholson GC, et al. Leptin directly regulates bone cell role in vitro and reduces os fragility in vivo. J Endocrinol. 2002 Nov;175(2):405–xv. [PubMed: 12429038]

6. Eghbali-Fatourechi Thou, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. 2003 Apr;111(eight):1221–30. [PMC free article: PMC152939] [PubMed: 12697741]

7. Elefteriou F, Takeda Due south, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, et al. Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci U Southward A. 2004 Mar 2;101(ix):3258–63. [PMC gratuitous article: PMC365777] [PubMed: 14978271]

8. Everts 5, Delaisse JM, Korper Westward, Jansen DC, Tigchelaar-Gutter Due west, Saftig P, Beertsen W. The bone lining cell: Its role in cleaning Howship'south lacunae and initiating bone formation. J Bone Miner Res. 2002 January;17(one):77–ninety. [PubMed: 11771672]

9. Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, Khosla S. Relative contributions of testosterone and estrogen in regulating os resorption and formation in normal elderly men. J Clin Invest. 2000 Dec;106(12):1553–60. [PMC free article: PMC381474] [PubMed: 11120762]

10. Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 5th Edition. Washington (DC): American Society for Bone and Mineral Inquiry; 2003.

11. Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE. Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am J Hum Genet. 2004 May;74(v):866–75. [PMC complimentary article: PMC1181981] [PubMed: 15077203]

12. Gong Y, Slee RB, Fukai North, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, et al. LDL receptor-related poly peptide five (LRP5) affects bone accrual and middle evolution. Cell. 2001 Nov 16;107(iv):513–23. [PubMed: 11719191]

13. Greyness H. Anatomy of the Human Body. Philadelphia: New York: Lea & Febiger; Bartleby.com; 1918. 2000 [cited 2004 Jun ix]. Bachelor from www​.bartleby.com/107/illus247.html.

14. Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res. 2001 Sep;16(nine):1575–82. [PubMed: 11547826]

15. Huang QY, Recker RR, Deng HW. Searching for osteoporosis genes in the post-genome era: Progress and challenges. Osteoporos Int. 2003 Sep;14(9):701–15. [PubMed: 12904838]

16. Jorgensen HL, Kusk P, Madsen B, Fenger M, Lauritzen JB. Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of os mass and fracture odds ratios. J Bone Miner Metab. 2004;22(two):132–viii. [PubMed: 14999524]

17. Kanis JA, Johansson H, Oden A, Johnell O, De Laet C, Melton LJ Three, Tenenhouse A, Reeve J, Silman AJ, Pols HA, Eisman JA, McCloskey EV, Mellstrom D. A meta-analysis of prior corticosteroid use and fracture run a risk. J Bone Miner Res. 2004 Jun;xix(6):893–99. [PubMed: 15125788]

18. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001 Dec;142(12):5050–5. [PubMed: 11713196]

19. Klein RF, Allard J, Avnur Z, Nikolcheva T, Rotstein D, Carlos Equally, Shea Thou, Waters RV, Belknap JK, et al. Regulation of bone mass in mice past the lipoxygenase gene Alox15. Science. 2004 Jan 9;303(5655):229–32. [PubMed: 14716014]

20. Kontulainen South, Sievanen H, Kannus P, Pasanen Grand, Vuori I. Effect of long-term bear upon-loading on mass, size, and estimated strength of humerus and radius of female racquet-sports players: A peripheral quantitative computed tomography study between young and erstwhile starters and controls. J Bone Miner Res. 2003 Feb;18(ii):352–9. [PubMed: 12568413]

21. Lee 1000, Jessop H, Suswillo R, Zaman G, Lanyon L. Endocrinology: Bone adaptation requires oestrogen receptor. Nature. 2003;424:389. [PubMed: 12879058]

22. Trivial RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Beau PM, Zhao SC, Eustace B, et al. A mutation in the LDL receptor-related protein 5 cistron results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002 Jan;70(1):eleven–nine. Epub 2001 Dec 03. [PMC free article: PMC419982] [PubMed: 11741193]

23. Lu H, Kraut D, Gerstenfeld LC, Graves DT. Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation. Endocrinology. 2003 Jan;144(1):346–52. [PubMed: 12488363]

24. Marcus R, Feldman D, Kelsey J, editors. Osteoporosis. Second Edition. Vol. 2. San Diego (CA): Academic Printing; 2001. pp. 207–27.

25. Mundy GR, Guise TA. Hormonal control of calcium homeostasis. Clin Chem. 1999 Aug;45(8 Pt ii):1347–52. [PubMed: 10430817]

26. Norman AW, Okamura WH, Bishop JE, Henry HL. Update on biological actions of 1alpha,25(OH)(2)-vitamin D(3) (rapid effects) and 24R,25(OH)(ii)-vitamin D(3). Mol Jail cell Endocrinol. 2002 Nov 29:197, ane–2, one–thirteen. [PubMed: 12431790]

27. Osteoporosis Prevention, Diagnosis, and Therapy. NIH Consensus Statement Online. 2000 March 27–29;17(1):136. [cited 2004 Mar 26]

28. Parfitt AM. The bone remodeling compartment: A circulatory office for os lining cells. J Os Miner Res. 2001 Sep;16(9):1583–5. [PubMed: 11547827]

29. Raisz LG, Rodan GA. Pathogenesis of osteoporosis. Endocrinol Metab Clin North Am. 2003 Mar;32(1):15–24. [PubMed: 12699290]

30. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004 Apr 24;363(9418):1377–85. [PubMed: 15110498]

31. Rubin MR, Cosman F, Lindsay R, Bilezikian JP. The anabolic effects of parathyroid hormone. Osteoporos Int. 2002;13(4):267–77. [PubMed: 12030541]

32. Schett G, Kiechl South, Redlich Grand, Oberhollenzer F, Weger Due south, Egger K, Mayr A, Jocher J, Xu Q, Pietschmann P, et al. Soluble RANKL and risk of nontraumatic fracture. JAMA. 2004 Mar 3;291(9):1108–13. [PubMed: 14996780]

33. Seeman E. Periosteal bone formation—a neglected determinant of bone strength. N Engl J Med. 2003 Jul 24;349(4):320–three. [PubMed: 12878736]

34. Sexton PM, Findlay DM, Martin TJ. Calcitonin. Curr Med Chem. 1999 Nov;6(eleven):1067–93. [PubMed: 10519914]

35. Stewart A F. Hyperparathyroidism, humoral hypercalcemia of malignancy, and the anabolic deportment of parathyroid hormone and parathyroid hormone-related protein on the skeleton. J Bone Miner Res. 2002 May;17(5):758–62. [PubMed: 12009005]

36. Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, et al. Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol. 2003 December;one(3):E69. [PMC complimentary article: PMC270020] [PubMed: 14691541]

37. Suzuki K, Miyakoshi N, Tsuchida T, Kasukawa Y, Sato Thousand, Itoi E. Furnishings of combined treatment of insulin and homo parathyroid hormone (i–34) on cancellous os mass and structure in streptozotocin-induced diabetic rats. Os. 2003 Jul;33(1):108–14. [PubMed: 12919705]

38. Vestergaard P, Mosekilde L. Fractures in patients with hyperthyroidism and hypothyroidism: A nationwide follow-upwards study in 16,249 patients. Thyroid. 2002 May;12(5):411–nine. [PubMed: 12097203]

39. Yakar Southward, Rosen CJ. From mouse to human being: Redefining the role of insulin-similar growth gene-I in the acquisition of bone mass. Exp Biol Med (Maywood). 2003 Mar;228(3):245–52. [PubMed: 12626768]

40. Wang J, Zhou J, Cheng CM, Kopchick JJ, Bondy CA. Prove supporting dual, IGF-I-contained and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. J Endocrinol. 2004 Feb;180(2):247–55. [PubMed: 14765976]

maloneyhisibut.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/books/NBK45504/