Pathophysiology

Normal Physiology of Bone

Bone is a dynamic tissue that has two major functions — namely, to serve as a supporting structure to allow movement and protection of various organs (e.g., lungs and brain) and attachment of muscles, and also to provide a storage bank of:

• inorganic elements (e.g., calcium and phosphorus) for mineral homeostasis
• blood-producing cells (e.g., red marrow) [Einhorn, 1996]

The cells of the skeleton, the extracellular matrix, and calcium-regulating hormones (parathyroid hormone [PTH] and vitamin D) work together to achieve and maintain these functions.

Structural Regions of Bone

Bone is not completely solid. The spaces between its hard components provide channels for blood vessels that supply bone cells with nutrients. Depending on the size of the spaces, the regions of a bone may be classified as cortical (compact) or trabecular (spongy, cancellous) bone (see figure below). Cortical bone makes up the thick outer shell of the bone, and trabecular bone is a system of thin plates encased within the shell. About 80% of the skeleton is made up of cortical bone, and the remaining 20% consists of trabecular bone [Marcus, 1994].

Trabecular and cortical bone consist of cells that are embedded in an organic and inorganic matrix. The organic matrix — osteoid — primarily consists of a protein called collagen, which is responsible for the elasticity, flexibility, and tensile strength of bone in response to pulling forces [Robey and Boskey, 1996; Shier et al., 1996]. The inorganic matrix of bone consists of various calcium salts, primarily hydroxyapatite, Ca₁₀(PO₄)₆OH₂, which are deposited in crystals within and between collagen. This inorganic matrix gives bone its rigidity, hardness, and strength in compression [Shier et al., 1996]. These organic and inorganic components are arranged differently between trabecular and cortical bone, and thus result in distinct properties.

Structural Regions of Bone

From Shier et al. [1996]; with permission.
Click on image for larger version.

Cortical bone

Also known as compact bone, cortical bone has a compact, organized structure and forms the cortex of bones. The basic unit of cortical bone is the osteon. Each osteon has a cylinder-shaped appearance and is built around an osteonic canal. This central canal contains one or two blood vessels [Einhorn, 1996; Shier et al., 1996].

Rings of intercellular material (concentric lamellae) surround the osteonic canals. Embedded in this material are the individual osteocytes, which are located in small spaces (lacunae) and are connected to other cells by radiating canaliculi [Baron, 1999]. The canaliculi form intricate pathways throughout the bone, which provide nourishment to osteocytes and remove waste products from these cells.

Osteons are arranged so that the osteonic canals travel the length of the bone. Transverse canals (Volkmann's canals) connect the osteonic canals (see figure below) and provide communication between the bone surface and medullary cavity [Shier et al., 1996].

Trabecular bone

Trabecular bone is also known as cancellous or spongy bone. It is made up of an irregular array of bony plates, resembling latticework, called trabeculae (see figure below), which are made up of osteocytes and intercellular material. Trabecular bone is prominent near the ends of the long bones and in the vertebral bodies [Einhorn, 1996].

Unlike cortical bone in which the osteocytes are located around osteonic canals, the osteocytes are arranged within the trabeculae. These cells perform the daily cellular activities that make the bone a viable, functioning tissue. The osteocytes receive nutrients through small channels in the trabeculae called canaliculi, which extend from the bone cells to the surface of the trabeculae. In some bones, the spaces between the trabeculae are filled with red bone marrow. The red marrow contains cells that are responsible for the production of blood cells.

Because trabecular bone consists of a network of spaces, it is not as tightly packed as cortical bone. It is arranged along the line of the most constant loading stress force that the force of gravity (the stress lines) exerts on the bone. Trabecular bone is strong and resilient when subjected to the forces of compression at the ends of bones and in the areas of the joint. This degree of organization of both the trabecular and cortical bone is related to the function of the individual bone cells that control the synthesis and breakdown of bone.

Structure of Bone

From Shier et al. [1996]; with permission.
Click on image for larger version.

Types of Bone Cells

There are four major types of bone cells: osteoblasts, osteocytes, lining cells, and osteoclasts. Osteocytes and lining cells are derived from osteoblasts [Lian et al., 1999]. Osteoclasts are derived from monocyte cells — thus they have a macrophage origin [Teitelbaum et al., 1996]. Each cell type has certain features that enable it to play different roles in bone metabolism. The following figure shows the relative locations of the four kinds of cells in the bone tissue.

Primary Types of Cells in Bone Tissue

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Osteoblasts

Osteoblasts are primarily responsible for bone formation and are derived from local mesenchymal stem cells. Osteoblasts are located on the outer surfaces of bone tissue where new bone is created (see above figure). Osteoblasts form a contiguous layer of cells that, in their active state, are cuboid in shape. As formation progresses, the number of osteoblasts decreases at the site and the cells become flattened. Each osteoblast has a large nucleus, many mitochondria, and a well-developed Golgi apparatus. These organelles are associated with the secretory functions of the osteoblast. The mitochondria provide the energy for cellular activities. The Golgi apparatus secretes substances that are released from the cells. Osteoblasts synthesize and secrete organic matrix for new bone, which largely contains collagen. Osteoblasts are always found lining a layer of bone matrix that they are producing and that is not yet calcified [Lian et al., 1999].

Osteoblasts work together to form seams of osteoid on preexisting mineralized surfaces, such as on bone in adults and on calcified cartilage in children. Once the seams reach a certain thickness, mineralization occurs between the osteoid and the mineralized surface (lag time is about 10 days). Adequate supplies of calcium and phosphate in the extracellular fluid are necessary for mineralization. Osteoblasts synthesize and release bone-specific alkaline phosphatase and osteocalcin. They also contain receptors for parathyroid hormone (PTH) and vitamin D.

Osteoblastic activity occurs continuously in all living bones; therefore, some new bone is constantly being formed. The lifespan of a team of osteoblasts at a particular site ranges from 3 months to 1.5 years. As bone formation slows, osteoblasts become incorporated into bone as osteocytes or remain on the surface as lining cells [Lian et al., 1999].

Osteocytes

Osteocytes are osteoblasts that become entrapped in the newly formed bone matrix. Osteocytes reside in lacunae, spaces within either the osteoid or the bony tissue. Once osteocytes are entrapped, they lose their ability to secrete the matrix. The osteocyte also develops long fine meshwork processes, or narrow channels, that form a network of communication with adjacent osteocytes and bone surface cells, such as osteoblasts, lining cells, and osteoclasts [Lian et al., 1999] (see above figure).

The role of osteocytes is not clearly defined. However, they may play a role in the nonosteoclast-mediated release of mineral from bone tissue. The long processes enable each osteocyte to receive hormonal signals that indicate the need to transfer minerals (e.g., calcium and phosphate) from the surrounding matrix. Historically, osteocytes were believed to be important in mineral homeostasis (nonhormonal and hormonal); however, their role in this area is now considered uncertain.

Lining cells

Also derived from osteoblasts, lining cells are flat or elongated cells found on the surface of the bone (see above figure) [Lian et al., 1999]. Lining cells may also be known as resting surface cells. The lining cells may secrete enzymes that clear away a thin area of bone sufficient to permit osteoclasts to begin bone removal, or resorption.

Osteoclasts

Osteoclasts are quite different from osteoblasts, osteocytes, and lining cells. They are derived from monocytes circulating in the bloodstream and are distinctly larger and have multiple nuclei resulting from fusion of precursor cells. The function of osteoclasts lies in bone resorption rather than bone formation and growth [Lian et al., 1999]. Resorption is a physiologic process that results in the loss of bone. Osteoclasts have a discoid shape with a ruffled border and are located on the surfaces of bone in shallow pits called Howship's lacunae in trabecular bone, or cylindrical tunnels in cortical bone (see above figure). These pits are created as osteoclasts resorb bone. The lifespan of an osteoclast may be as long as 7 weeks.

The ruffled border contains elements that resorb organic and inorganic components of bone. As the ruffled border adheres to the bone surface, it creates a "sealing zone" or "clear zone" under the cell. It then secretes enzymes that acidify the area under the ruffled border, decalcifying the bone, and other enzymes that digest bone [Lian et al., 1999]. The process of decalcification and the breakdown of osteoid results in a saucer-shaped depression in the bone surface (Howship's lacuna) [Einhorn, 1996; Marcus, 1994]. Resorption releases calcium from the bone to the blood and allows bone modeling and remodeling to occur. The average duration of a resorption site is about 4 weeks in humans.

Bone Modeling and Remodeling

The processes of bone formation by osteoblasts and bone resorption by osteoclasts produce opposite results – formation produces bone mass and resorption reduces bone mass. These processes can work in two ways. First, they can work at the same time on different surfaces; the net effect is an increase in bone. This process is called modeling and is responsible for shaping or sculpting the skeleton during growth. Second, they can work together on the same area but at different times to renew bone; the net effect is no change or a net loss. This process is called remodeling and is responsible for removing old bone and forming new bone [Einhorn, 1996].

Modeling begins during infancy and childhood, whereas remodeling continues during adulthood [Einhorn, 1996]. During infancy and childhood, bones grow and attain mature size and shapes. The osteoblast usually does more work than the osteoclast because the net effect is an increase in bone mass. Modeling is age dependent. It slows during adolescence and is nonexistent by the midtwenties. At this point, remodeling activity increases. Old bone is continually resorbed and new bone tissue is formed in its place [Einhorn, 1996]. Like the skin, bone replaces itself throughout life. As a person ages, repeated strain or stress on bone from ordinary mechanical use, such as physical activity, results in the development of microdamage. Accumulation of microdamage can reduce the strength of bone, and therefore, remodeling is necessary to repair the damage. Remodeling allows the microdamage of worn or injured bone to be replaced and helps to maintain skeletal strength. Any substantial decrease in the rate of remodeling may increase the risk of spontaneous fractures because the skeleton's ability to repair itself is decreased.

Remodeling involves both the osteoclasts and osteoblasts. Osteoclasts are stimulated to resorb bone at specific sites, and osteoblasts are activated to replace the bone. The two processes are "coupled" (bone resorption is followed by bone formation) [Einhorn, 1996]. Postmenopausal women not taking estrogen have net bone loss because resorption is greater than formation. In cortical bone, osteoclasts create resorption tunnels parallel to the long axis of the bone and the osteoblasts fill in the tunnel with new bone. In trabecular bone, osteoclasts create shallow excavations toward the center, which the osteoblasts then fill in with new bone. In remodeling, bone formation by the osteoblast always follows osteoclastic resorption at the same resorption site. The site at which active bone remodeling takes place is known as a bone remodeling unit (BRU) or bone multicellular unit. In normal circumstances, the entire volume of bone that is resorbed is replaced in both cortical and trabecular bone. In an average-sized skeleton, one new BRU is initiated [Einhorn, 1996] and one is completed about every 10 seconds.

In trabecular bone it takes 3-6 months to complete a remodeling cycle, with about 1 month for resorption followed by 5 months for formation [Baron, 1999]. It is estimated that the remodeling cycle takes longer in cortical bone [Einhorn, 1996]. The number of remodeling units activated within a given space over a given period of time determines the rate of bone turnover. Although trabecular bone represents only 20% of skeletal mass, it represents 80% of bone turnover because of its large surface area-to-mass ratio. This is a far greater percentage of bone turnover compared with cortical bone, which makes up 80% of skeletal mass and accounts for only 20% of total bone turnover in a given period.

Stages of bone remodeling

Remodeling is estimated to account for replacement of 20% of the adult skeleton each year and can be divided into five distinct phases:

 
1. activation
2. resorption
3. reversal
4. formation
5. resting

The remodeling cycle is demonstrated in the following figure.

Remodeling Cycle

Click on image for animation/larger version.

Mineral Homeostasis

A steady supply of calcium and, to a lesser extent, a supply of phosphorus are needed to perform the daily functions of the body. A sufficient supply of calcium must be maintained in the blood at all times for normal muscle, bone, and nerve function, and sufficient levels of calcium must be maintained in the bone for growth and repair [Guyton and Hall, 2000]. This process of maintaining adequate supplies of calcium and other minerals is called mineral homeostasis.

The body accomplishes mineral homeostasis in several ways. The focus in this section is on two of these processes:

• bone-blood transfer
• osteoclast-mediated bone remodeling.

Bone-blood transfer

The skeletal and circulatory systems maintain an intimate association. Bone tissue requires a steady supply of nutrients (e.g., minerals, proteins, and oxygen), which the blood vessels that penetrate the bone and branch into capillaries transport. Besides supplying nutrients to the osteocytes, the capillaries carry away waste products (e.g., carbon dioxide) and minerals (e.g., calcium and phosphorus). The osteocytes may release calcium and phosphorus into the extracellular fluid space between themselves and the capillaries. The capillaries absorb these substances and carry them into the bloodstream. This bone-blood transfer also works in the opposite direction, as substances in the blood are transported to the osteocytes.

Calcium is an essential substance in body metabolism as well as an important part of bone structure. It is necessary for proper muscle contraction and nerve impulse conduction. Even a slight decline in the circulating level of calcium can cause the nerves and muscles to spasm. Thus, sufficient calcium must be available for normal body functions [Guyton and Hall, 2000].

Calcium intake has been identified as a possible determinant of fracture risk in osteoporosis. A partial protective effect against bone loss has been demonstrated in postmenopausal women receiving calcium supplements. However, a direct association between calcium intake and the occurrence of fractures has not been shown.

The body's main source of calcium is the diet. Unfortunately, very few foods contain significant amounts of calcium. Milk and dairy products supply the majority of calcium in most diets. If adequate calcium intake is not obtained, calcium is removed from the skeleton, the body's primary storage reservoir for calcium, to maintain adequate serum levels. The skeleton contains 1000 g (1 kg) of calcium, or 99% of the body's supply. Each day, about 500 mg (0.50 g) of calcium enter and leave the skeletal bones. Under normal conditions, the gut – mostly the small intestine – absorbs only a fraction of the daily calcium intake. Besides absorbing calcium, the gut also releases calcium by intestinal secretion, with net absorption being about 15-20% of calcium intake. The amount of dietary calcium that is absorbed depends on an individual's needs. Through adaptation, the body can adjust the amount of dietary calcium absorbed, particularly through the active form of vitamin D [Guyton and Hall, 2000]. Calcium absorption increases during growth periods and decreases with advancing age. Also, not all forms of calcium are equally absorbed. The gastrointestinal (GI) system ingests and processes food containing calcium and other nutrients. The calcium that is absorbed into the bloodstream is then circulated through the kidneys, whereas the remainder is excreted with waste products of the intestinal tract. The primary purpose of the kidneys is to filter waste substances from the blood and excrete them in the urine. The bulk of the calcium that normally enters the kidneys is reabsorbed back into the bloodstream with small amounts of calcium being excreted in the urine. However, the kidneys can exert significant control over calcium levels in the blood by reabsorbing more or less calcium.

Thus, the primary sites of calcium metabolism and homeostasis are bone, intestine, and kidney (see figure below). Overall homeostasis is maintained between these sites through the bloodstream, which maintains a constant calcium level in healthy individuals.

Calcium Homeostasis Regulation of Bone Remodeling

Adapted from Shier et al. [1996]; with permission.
Click on image for larger version.

Regulation of bone remodeling

Bone remodeling is regulated by hormonal, nutritional, metabolic, and mechanical factors. Although it is difficult to separate these factors, the following discussion focuses primarily on the regulation of bone remodeling by hormones.

Effect of parathyroid hormone on bone remodeling

The parathyroid glands secrete PTH, also called parathormone, a substance that causes an increase in blood calcium levels and a decrease in blood phosphate levels. There are four parathyroid glands located on the posterior surface of the thyroid gland. The thyroid gland is located just below the larynx and in front of the trachea [Shier et al., 1996]. The figure below shows the location of these important glands.

Each parathyroid gland consists of tightly packed secretory cells that are associated with capillaries. PTH is secreted into the bloodstream and transported to the target tissues (e.g., bone and kidney).

Parathyroid and Thyroid Glands (posterior view)

From Shier et al. [1996]; with permission.
Click on image for larger version.

PTH is secreted from the parathyroid glands in response to a decrease in blood calcium levels. It causes a subsequent increase in blood calcium levels by three mechanisms:

1. increased reabsorption of calcium and decreased reabsorption of phosphate from urine via the kidneys
2. increased bone resorption, which results in the release of calcuim from bone
3. increased formation by the kidney of the active form of vitamin D (1,25 dihydroxycholecalciferol). Vitamin D increases intestinal calcium absorption.

The following figure summarizes the effects of PTH. The secretion of PTH by the parathyroid glands is regulated by a negative feedback mechanism based on the blood calcium level. As the calcium level increases, less PTH is secreted; as the calcium level decreases, more PTH is released [Shier et al., 1996]. PTH causes increased osteoclast-mediated bone resorption and movement of calcium into the extracellular fluid. Paradoxically, the receptors for PTH are on osteoblasts rather than osteoclasts. It is believed that PTH activation of osteoblasts results in their release of factor(s) that activate osteoclasts.

Effects of PTH

Adapted from Shier et al. [1996]; with permission.
Click on image for larger version.

The kidney will react first because it is the most sensitive and has the fastest mechanism. The skeletal response is usually less sensitive and slower. Although the kidney is probably the main regulator of blood calcium in the short term, the skeleton is the major regulator for long-term homeostasis. Calcium absorption from the intestine may vary among individuals because it depends on dietary intake and the level of 1,25-dihydroxycholecalciferol (active form of vitamin D). Calcium from the intestine is usually used to replace the calcium that is withdrawn from the bones. Calcium level in the blood is the primary regulator of PTH secretion.

Effect of PTH on kidneys

PTH causes the kidneys to conserve calcium and raise the blood calcium level by excreting less calcium in the urine. At the same time, PTH diminishes phosphate reabsorption and promotes excretion of phosphate in the urine. The main overall effect of PTH with respect to phosphate stems from its effect on the kidney [Guyton and Hall, 2000].

Effect of PTH on bone resorption

PTH secretion results in the release of calcium from bone and an increase in blood calcium levels. The mechanisms that play a role in the transfer of calcium from bone to the bloodstream are:

1. osteocyte-mediated short-term exchange between blood and bone (possibly)
2. osteoclast-mediated bone resorption.

Besides the action of PTH on bone, there is nonhormonally mediated exchange of calcium between bone and the extracellular fluid. PTH secretion is responsible for the fine-tuning of the blood calcium [Guyton and Hall, 2000].

Effect of PTH on the intestine

PTH also enhances intestinal absorption of both calcium and phosphorus by influencing the metabolism of vitamin D. PTH stimulates the kidneys to produce the active form of vitamin D – 1,25-dihydroxycholecalciferol. Vitamin D controls the mechanism by which calcium is absorbed from the intestine. Therefore, PTH increases vitamin D, which increases intestinal calcium absorption.

Effect of vitamin D on bone remodeling

Vitamin D, or cholecalciferol, plays an important role in the intestinal absorption of calcium, thus enhancing bone formation. Vitamin D can be obtained directly from the diet or synthesized in the body. It is considered to be a hormone and a vitamin.

The synthesis of vitamin D begins with cholesterol, which is obtained in the diet or synthesized endogenously. Cholesterol is converted into provitamin D (dehydrocholesterol) and stored in the skin. When the skin is exposed to sunlight, the provitamin is converted to vitamin D. Most people who live in temperate climates have adequate exposure to sunlight and fulfill their daily requirement for vitamin D in this manner. Elderly people who become housebound are at risk for hip fractures in part because of low vitamin D levels (decreased sunlight or intake).

Vitamin D is metabolized in the liver and kidney. In the liver, vitamin D is changed to 25-hydroxycholecalciferol. The kidney converts it to the active form of vitamin D, 1,25-dihydroxycholecalciferol. The active form can only be made in the presence of PTH. The active form of vitamin D controls the mechanism by which calcium is absorbed from the intestine. Thus, PTH indirectly regulates intestinal calcium absorption by causing the kidneys to produce the active form of vitamin D [Guyton and Hall, 2000]. The role of vitamin D is summarized in the following figure.

Role of Vitamin D

From Shier et al. [1996]; with permission.
Click on image for larger version.

Effect of calcitonin on bone remodeling

The hormone calcitonin, which the thyroid gland produces, acts as the physiologic antagonist to PTH. The major site of calcitonin action is the bone where it decreases osteoclast activity through calcitonin receptors on the osteoclast.

These effects of calcitonin on blood calcium levels are mainly temporary, lasting for a few hours to a few days. Calcitonin also has minor effects on the kidney and intestinal tract. Again, these effects are opposite to those of PTH. The following figure summarizes the interaction between calcitonin and PTH [Guyton and Hall, 2000].

Regulation of the Secretion of PTH and Calcitonin

Adapted from Shier et al. [1996]; with permission.
Click on image for larger version.

Calcitonin, like PTH operates on a negative feedback system. When the blood calcium level rises, more calcitonin is secreted. However, calcitonin disappears rapidly from circulation, and may function primarily in short-term regulation. In the long term, the more powerful PTH mechanism overrides the action of calcitonin. The exact role of calcitonin in adults remains unknown. When the thyroid gland is removed and calcitonin is no longer secreted, there are no definite effects attributed to calcitonin deficiency. Conversely, for patients with medullary carcinoma of the thyroid (which secretes large amounts of calcitonin into the plasma) calcium homeostasis is normal [Kanis, 1994].

Effect of other hormones on bone remodeling

Several other hormones also act on bone, although their roles are less clearly understood. Thyroid hormone is necessary for normal bone growth and remodeling. Glucocorticoids, growth hormone, insulin, other growth factors, and sex hormones, particularly estrogen, affect bone. It is believed that estrogen inhibits bone resorption. The decline in estrogen levels after menopause is associated with net increases in bone resorption, a negative calcium balance, and a net loss of bone. Estrogen replacement therapy may prevent osteoporosis in postmenopausal women.

Bone Turnover in Osteoporosis

The underlying problem in osteoporosis is an imbalance between bone resorption and bone formation. In osteoporosis, bone resorption takes place to a greater extent than bone formation, so a negative balance occurs and results in a net loss of bone. This imbalance might occur as a result of one or a combination of the following factors:

• increased bone resorption within a remodeling unit
• decreased bone formation within a remodeling unit (incomplete coupling).

Besides an imbalance of resorption and formation within a remodeling unit, further bone loss may also occur as a result of an increase in the number of new remodeling units [Eastell, 1999].

Trabecular bone is metabolically more active than cortical bone. It also has a larger surface area because of the trabecular network of bony plates and spaces. Because bone remodeling depends on surface area and trabecular bone has an extensive surface, trabecular bone has a more rapid turnover than cortical bone [Einhorn, 1996]. Vertebrae, which have a large proportion of trabecular bone, are commonly the first sites to show bone loss in osteoporosis. Normal vertebrae contain a dense honeycomb structure with thick trabeculae, whereas osteoporotic bone has fewer and thinner trabeculae with loss of intertrabecular connections. The following figure demonstrates how osteoporosis can affect bone.

Trabecular Thinning, Breakage, and Perforation

Click on image for animation/larger version.

The vertebrae, proximal femur, and distal radius are particularly prone to osteoporotic fracture because these parts of the skeleton contain a large proportion of trabecular bone, relative to the entire skeleton, which contains 80% cortical bone and 20% trabecular bone.

The transition from normal to osteoporotic bone is caused by changes in bone remodeling. With increased age (especially after menopause), bone resorption occurs at an accelerated rate. Multinucleated giant cells, called osteoclasts, digest the bone surface to carry out resorption, which takes about 3 weeks. The osteoclasts leave behind an erosion cavity, or lacuna. Bone-producing cells, or osteoblasts, migrate to the cavity and fill in the defect. It may take 3-4 months to replenish the bone lost during resorption. If bone replacement is incomplete, the trabecular width decreases. In osteoporosis, extensive resorption perforates the trabeculae, leaving fewer surfaces on which to build. The spaces in the network become larger because the process of bone formation cannot replenish the amount of bone lost during resorption. The following figure provides the percentage of trabecular and cortical bone at selected skeletal sites [Bonnick, 1998].

Trabecular and Cortical Bone Content of Selected Skeletal Sites

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The measurement of biochemical markers of bone turnover can be used to assess bone metabolism. For detailed definition and understanding of the molecular basis of biochemical markers of bone turnover, refer to the discussion on "Biochemical Markers of Bone Turnover" in the Diagnosis section of the Osteoporosis Disease Module. The specific biochemical markers of bone turnover discussed include resportion markers from collagen degradation (urine hydroxyproline, urine total pyridinoline, urine total deoxypyridinoline, urine collagen type I cross-linked N-telopeptide, serum collagen type I cross-linked N-telopeptide, and urine collagen type I cross-linked C-telopeptide [crosslaps]). Biochemical markers of bone formation discussed include the bone formation markers from osteoblast secretion (serum osteocalcin, serum total alkaline phosphatase, serum bone-specific alkaline phosphatase) and those from collagen formation (serum procollagen I carboxyterminal propeptide [PICP] and serum procollagen type I N-termianl propeptide [PINP]).

Peak Bone Mass and Osteoporosis

Peak bone mass is the maximum mass of bone achieved by an individual at skeletal maturity, typically between ages 25 and 35. After peak bone mass is attained, both men and women lose bone mass over the remainder of their lifetimes. Because of the subsequent bone loss, peak bone mass is an important factor in the development of osteoporosis [Kanis, 1994].

Several factors determine an individual's peak bone mass:

• genetics – demonstrated in studies of twins and studies establishing a strong relationship between the bone mass of mothers and daughters [Kanis, 1994]
• gender – men have greater peak bone mass than women [Kanis, 1994]
• ethnic origin (e.g., people of African origin generally have higher bone mass than those of northern European origin) [Kanis, 1994]
• nutritional factors (e.g., calcium, vitamin D, protein intake) [Kanis, 1994]
• hormonal factors [Kanis, 1994]
• weight-bearing exercise
• other environmental factors (e.g., tobacco and alcohol consumption).

The stages of bone mass for women are shown below. The figure depicts the time during which active bone growth occurs and peak bone mass is attained. This is followed by a period of very slow and gradual decline in bone mass until the time of menopause when the rate of bone loss accelerates for several years. After about age 60, the rate of bone loss decreases [Wasnich et al., 1989].

The stages of bone loss for men and women follow the same progression. However, unlike men, women attain a lower peak bone mass and experience a sharp decline following menopause. The difference between men and women who have osteoporotic fractures and those who do not is related to the amount of bone they have between ages 25 and 35 (i.e., peak bone mass) and the rate of bone loss thereafter, plus other risk factors.

Stages of Bone Mass in the Life Cycle of Women

Adapted from Wasnich et al. [1989]; with permission.
Click on image for larger version.

Fractures in Osteoporosis

A fracture is any break in a bone. The clinical significance of osteoporosis is related to the types of fractures that occur, rather than the processes that give rise to osteoporotic bone. The classic osteoporotic fractures in women are vertebral compression fractures, fractures of the femur, and Colles' fracture of the wrist (see following figure) [Kanis, 1994].

Three Principal Sites of Osteoporotic Fractures

Click on image for animation/larger version.

Vertebral Fractures

The bodies of the vertebrae in the vertebral column are primarily structured to withstand compressive forces. Healthy vertebral bodies can be compressed to 66% of their original height before fracturing. Vertebral bodies with low bone mass and weakened trabeculae are unable to withstand stresses and are more prone to fracture.

Vertebral fractures are a significant component of osteoporosis because the first osteoporotic fractures typically occur in the central region of the spine (thoracic and lumbar vertebrae) during the early stages of the disease (see figure below). The thoracic and lumbar vertebrae bear most of the body weight and are susceptible to fracture if trabecular bone loss has occurred.

Side View of the Vertebral Column

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Vertebral fractures typically take one of three forms:

 
• biconcave fracture (end-plate deformity)
• wedge fracture
• total crush (compression) fracture.

Consequences of vertebral fractures

The consequences of vertebral fractures include kyphosis, lordosis, and loss of height. Continued fractures can result in the ribcage tilting downward toward the hips, thereby leading to a forward curvature of the upper spine (kyphosis). As this progresses, the lower spine curves inward (lordosis) and the abdomen protrudes to accommodate the internal organs. The result of this progression is a deformity known as the dowager's hump. A significant loss of height accompanies the progression of osteoporosis, and it is possible for women to lose several inches of height in a relatively short period of time [Kanis, 1994]. The total loss may be as much as 8 inches, all in the upper body (see following figure).

Progression of Osteoporosis in the Spine

From Sinaki and Mikkelsen [1984]; with permission.
Click on image for animation/larger version.

With each new series of vertebral fractures, patients may experience severe pain in a two-phase pattern. In the acute phase, intense pain occurs at the fracture site from the fracture itself and damage to surrounding tissues. This stage usually lasts from 1-4 weeks, until the bone adapts to the collapsed form. Following the acute phase is the chronic phase, which may last from 6 months to 1 year. The pain in this chronic phase is less severe, but persists because of muscle spasm and ligament strain. Although this two-phase pattern is common, many cases of vertebral fracture are asymptomatic. Many vertebral fractures are neither readily diagnosed nor detected by standard X-rays [Kanis, 1994].

Hip Fracture

The anatomy of the hip, particularly the femur, is shown in the following figure. In healthy individuals, the intertrochanteric region is made up almost equally of cortical and trabecular bone, whereas the femoral shaft contains mostly cortical bone. The high proportion of trabecular bone in the proximal femur (includes femoral neck, femoral head, and intertrochanteric region) is needed to withstand the load-bearing forces applied to the hip. In osteoporosis affecting the proximal femur, trabecular and cortical bone is lost, putting this region at greater risk of fracture.

Anatomy of the Hip

Click on image for larger version.

A hip fracture is a severe break of the femur (see figure below). The most common sites of osteoporotic hip fractures are the femoral neck, which is the weakest part of the bone, and the intertrochanteric region.

Types of Hip Fractures

Click on image for animation/larger version.

Although they may be the result of a fall, fractures also can occur spontaneously. Hip fractures are extremely painful and require immediate medical attention and hospitalization. After a hip fracture, serious and possibly fatal complications (e.g., massive hemorrhage or pulmonary embolism) can occur. If the neck of the femur is fractured and fails to heal, the head of the femur can lose its blood supply and die. This necessitates replacement with an artificial device. Hip fracture, therefore, is associated with significant morbidity and mortality. Based on several epidemiologic studies, it has been estimated that women who suffer an osteoporosis-related hip fracture have an excess mortality rate of about 20% from complications in the year following their fracture.

Also, half or more of surviving patients fail to regain their full, prefracture function, and many require institutional care. Thus, hip fracture has a major impact on both clinical and economic outcomes. Visual impairment, poor reflexes, and other neurologic dysfunction contribute, along with low bone density, to the high rate of hip fracture in the elderly [Kanis, 1994].

Wrist Fracture

Wrist fractures are usually the result of a fall on the outstretched hand. A Colles' fracture is a break in the lower end of the radius in which the lower bone fragment is displaced downward (see figure below).

Colles’ Fracture of the Wrist

Click on image for animation/larger version.

The peak incidence of Colles' fractures in postmenopausal women is between ages 60 and 70. The rate is stable thereafter, and this may be because older individuals are more likely to fall on the hip rather than the hand.

Although wrist fractures are seldom associated with fatalities and cause less morbidity than hip fractures, they are painful and require immobilization in a cast for 4-6 weeks. After a break is healed, physical therapy is needed to recover function. Moreover, mild to moderate residual pain (sometimes including a "burning" pain), stiffness of the wrist and fingers, osteoarthritic changes, and diminished function reportedly occur in 30% of patients [Kanis, 1994].

Histology of Bone Fracture

Fractures may result from disease states such as osteoporosis and accidents. Patients with osteoporosis have an increased risk of fracture from the loss of bone mass. Other risk determinants include age of bone and microfracture repair, which depends on bone remodeling.

Repair of Fractures

The repair of a fractured bone may require several months. The bone cells grow and reproduce slowly. Mineral deposition is a gradual process. Also, the blood supply may be disrupted by the fracture. This may increase the time required for healing.

The following figure shows the major stages in the repair of a fracture. The sequence of events that occur in the repair of a fracture includes:

1. The blood vessels and periosteum at the site of injury are torn and ruptured. Within hours of a fracture, blood spreads through the area and forms a hematoma (a).
2. Developing blood vessels and large numbers of osteoblasts invade the hematoma. The osteoblasts multiply rapidly and begin producing trabecular bone. Fibrocartilage also fills the damaged area and becomes a model for new bone tissue (b). Also, osteoclasts will aid by reabsorbing bone fragments.
3. When fibrocartilage fills the gaps between the ends of the fractured bone, the area is called a callus (c). The cartilage is then replaced with trabecular bone.
4. More bone tissue is produced than needed to replace the damaged tissue. In the final phase, osteoclasts remove excess bone tissue. The repaired bone is shaped like the original bone through the remodeling process (d) [Shier et al., 1996].

The rate at which repair occurs depends on several conditions, namely the nature of the injury, the distance between the broken ends, the specific bone that is broken, and the patient's age. As the patient grows older, the time required for healing is greater. In the elderly population, fractures are associated with high rates of morbidity and mortality. The treatment of fractures imposes a significant economic burden on health care resources and will continue to do so in the future.

Repair of a Fracture

From Shier et al. [1996]; with permission.
Click on image for larger version.

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