Bone

Cross-section details of a long bone

The hard outer layer of bones is composed of cortical bone, which is also called compact bone as it is much denser than cancellous bone. It forms the hard exterior (cortex) of bones. The cortical bone gives bone its smooth, white, and solid appearance, and accounts for 80% of the total bone mass of an adult human skeleton.[6] It facilitates bone's main functions—to support the whole body, to protect organs, to provide levers for movement, and to store and release chemical elements, mainly calcium. It consists of multiple microscopic columns, each called an osteon or Haversian system. Each column is multiple layers of osteoblasts and osteocytes around a central canal called the haversian canal. Volkmann's canals at right angles connect the osteons together. The columns are metabolically active, and as bone is reabsorbed and created the nature and location of the cells within the osteon will change. Cortical bone is covered by a periosteum on its outer surface, and an endosteum on its inner surface. The endosteum is the boundary between the cortical bone and the cancellous bone.[7] The primary anatomical and functional unit of cortical bone is the osteon.

Micrograph of cancellous bone

Cancellous bone, also called trabecular or spongy bone,[7] is the internal tissue of the skeletal bone and is an open cell porous network. Cancellous bone has a higher surface-area-to-volume ratio than cortical bone and it is less dense. This makes it weaker and more flexible. The greater surface area also makes it suitable for metabolic activities such as the exchange of calcium ions. Cancellous bone is typically found at the ends of long bones, near joints and in the interior of vertebrae. Cancellous bone is highly vascular and often contains red bone marrow where hematopoiesis, the production of blood cells, occurs. The primary anatomical and functional unit of cancellous bone is the trabecula. The trabeculae are aligned towards the mechanical load distribution that a bone experiences within long bones such as the femur. As far as short bones are concerned, trabecular alignment has been studied in the vertebral pedicle.[8] Thin formations of osteoblasts covered in endosteum create an irregular network of spaces,[9] known as trabeculae. Within these spaces are bone marrow and hematopoietic stem cells that give rise to platelets, red blood cells and white blood cells.[9] Trabecular marrow is composed of a network of rod- and plate-like elements that make the overall organ lighter and allow room for blood vessels and marrow. Trabecular bone accounts for the remaining 20% of total bone mass but has nearly ten times the surface area of compact bone.[10]

The words cancellous and trabecular refer to the tiny lattice-shaped units (trabeculae) that form the tissue. It was first illustrated accurately in the engravings of Crisóstomo Martinez.[11]

Bone marrow, also known as myeloid tissue in red bone marrow, can be found in almost any bone that holds cancellous tissue. In newborns, all such bones are filled exclusively with red marrow or hematopoietic marrow, but as the child ages the hematopoietic fraction decreases in quantity and the fatty/ yellow fraction called marrow adipose tissue (MAT) increases in quantity. In adults, red marrow is mostly found in the bone marrow of the femur, the ribs, the vertebrae and pelvic bones.[12]

Bone cells

Bone is a metabolically active tissue composed of several types of cells. These cells include osteoblasts, which are involved in the creation and mineralization of bone tissue, osteocytes, and osteoclasts, which are involved in the reabsorption of bone tissue. Osteoblasts and osteocytes are derived from osteoprogenitor cells, but osteoclasts are derived from the same cells that differentiate to form macrophages and monocytes.[13] Within the marrow of the bone there are also hematopoietic stem cells. These cells give rise to other cells, including white blood cells, red blood cells, and platelets.[14]

Light micrograph of decalcified cancellous bone tissue displaying osteoblasts actively synthesizing osteoid, containing two osteocytes.

Osteoblasts are mononucleate bone-forming cells. They are located on the surface of osteon seams and make a protein mixture known as osteoid, which mineralizes to become bone.[15] The osteoid seam is a narrow region of newly formed organic matrix, not yet mineralized, located on the surface of a bone. Osteoid is primarily composed of Type I collagen. Osteoblasts also manufacture hormones, such as prostaglandins, to act on the bone itself. The osteoblast creates and repairs new bone by actually building around itself. First, the osteoblast puts up collagen fibers. These collagen fibers are used as a framework for the osteoblasts' work. The osteoblast then deposits calcium phosphate which is hardened by hydroxide and bicarbonate ions. The brand-new bone created by the osteoblast is called osteoid.[16] Once the osteoblast is finished working it is actually trapped inside the bone once it hardens. When the osteoblast becomes trapped, it becomes known as an osteocyte.[17] Other osteoblasts remain on the top of the new bone and are used to protect the underlying bone, these become known as lining cells.

Osteocytes are cells of mesenchymal origin and originate from osteoblasts that have migrated into and become trapped and surrounded by bone matrix that they themselves produced.[7] The spaces the cell body of osteocytes occupy within the mineralized collagen type I matrix are known as lacunae, while the osteocyte cell processes occupy channels called canaliculi. The many processes of osteocytes reach out to meet osteoblasts, osteoclasts, bone lining cells, and other osteocytes probably for the purposes of communication.[18] Osteocytes remain in contact with other osteocytes in the bone through gap junctions—coupled cell processes which pass through the canalicular channels.

Osteoclasts are very large multinucleate cells that are responsible for the breakdown of bones by the process of bone resorption. New bone is then formed by the osteoblasts. Bone is constantly remodeled by the resorption of osteoclasts and created by osteoblasts.[13] Osteoclasts are large cells with multiple nuclei located on bone surfaces in what are called Howship's lacunae (or resorption pits). These lacunae are the result of surrounding bone tissue that has been reabsorbed.[19] Because the osteoclasts are derived from a monocyte stem-cell lineage, they are equipped with phagocytic-like mechanisms similar to circulating macrophages.[13] Osteoclasts mature and/or migrate to discrete bone surfaces. Upon arrival, active enzymes, such as tartrate-resistant acid phosphatase, are secreted against the mineral substrate. The reabsorption of bone by osteoclasts also plays a role in calcium homeostasis.[19]

Bones consist of living cells (osteoblasts and osteocytes) embedded in a mineralized organic matrix. The primary inorganic component of human bone is hydroxyapatite, the dominant bone mineral, having the nominal composition of Ca₁₀(PO₄)₆(OH)₂.[20] The organic components of this matrix consist mainly of type I collagen—"organic" referring to materials produced as a result of the human body—and inorganic components, which alongside the dominant hydroxyapatite phase, include other compounds of calcium and phosphate including salts. Approximately 30% of the acellular component of bone consists of organic matter, while roughly 70% by mass is attributed to the inorganic phase.[21] The collagen fibers give bone its tensile strength, and the interspersed crystals of hydroxyapatite give bone its compressive strength. These effects are synergistic.[21] The exact composition of the matrix may be subject to change over time due to nutrition and biomineralization, with the ratio of calcium to phosphate varying between 1.3 and 2.0 (per weight), and trace minerals such as magnesium, sodium, potassium and carbonate also being found.[21]

Type I collagen composes 90–95% of the organic matrix, with remainder of the matrix being a homogenous liquid called ground substance consisting of proteoglycans such as hyaluronic acid and chondroitin sulfate,[21] as well as non-collagenous proteins such as osteocalcin, osteopontin or bone sialoprotein. Collagen consists of strands of repeating units, which give bone tensile strength, and are arranged in an overlapping fashion that prevents shear stress. The function of ground substance is not fully known.[21] Two types of bone can be identified microscopically according to the arrangement of collagen: woven and lamellar.

• Woven bone (also known as fibrous bone), which is characterized by a haphazard organization of collagen fibers and is mechanically weak.[22]
• Lamellar bone, which has a regular parallel alignment of collagen into sheets ("lamellae") and is mechanically strong.[22]

Transmission electron micrograph of decalcified woven bone matrix displaying characteristic irregular orientation of collagen fibers

Woven bone is produced when osteoblasts produce osteoid rapidly, which occurs initially in all fetal bones, but is later replaced by more resilient lamellar bone. In adults woven bone is created after fractures or in Paget's disease. Woven bone is weaker, with a smaller number of randomly oriented collagen fibers, but forms quickly; it is for this appearance of the fibrous matrix that the bone is termed woven. It is soon replaced by lamellar bone, which is highly organized in concentric sheets with a much lower proportion of osteocytes to surrounding tissue. Lamellar bone, which makes its first appearance in humans in the fetus during the third trimester,[23] is stronger and filled with many collagen fibers parallel to other fibers in the same layer (these parallel columns are called osteons). In cross-section, the fibers run in opposite directions in alternating layers, much like in plywood, assisting in the bone's ability to resist torsion forces. After a fracture, woven bone forms initially and is gradually replaced by lamellar bone during a process known as "bony substitution." Compared to woven bone, lamellar bone formation takes place more slowly. The orderly deposition of collagen fibers restricts the formation of osteoid to about 1 to 2 µm per day. Lamellar bone also requires a relatively flat surface to lay the collagen fibers in parallel or concentric layers.[24]

The extracellular matrix of bone is laid down by osteoblasts, which secrete both collagen and ground substance. These synthesise collagen within the cell, and then secrete collagen fibrils. The collagen fibers rapidly polymerise to form collagen strands. At this stage they are not yet mineralised, and are called "osteoid". Around the strands calcium and phosphate precipitate on the surface of these strands, within days to weeks becoming crystals of hydroxyapatite.[21]

In order to mineralise the bone, the osteoblasts secrete vesicles containing alkaline phosphatase. This cleaves the phosphate groups and acts as the foci for calcium and phosphate deposition. The vesicles then rupture and act as a centre for crystals to grow on. More particularly, bone mineral is formed from globular and plate structures.[25][26]

Structure of a long bone

One way to classify bones is by their shape or appearance.

There are five types of bones in the human body: long, short, flat, irregular, and sesamoid.[27]

• Long bones are characterized by a shaft, the diaphysis, that is much longer than its width; and by an epiphysis, a rounded head at each end of the shaft. They are made up mostly of compact bone, with lesser amounts of marrow, located within the medullary cavity, and areas of spongy, cancellous bone at the ends of the bones.[28] Most bones of the limbs, including those of the fingers and toes, are long bones. The exceptions are the eight carpal bones of the wrist, the seven articulating tarsal bones of the ankle and the sesamoid bone of the kneecap. Long bones such as the clavicle, that have a differently shaped shaft or ends are also called modified long bones.
• Short bones are roughly cube-shaped, and have only a thin layer of compact bone surrounding a spongy interior. The bones of the wrist and ankle are short bones.
• Flat bones are thin and generally curved, with two parallel layers of compact bones sandwiching a layer of spongy bone. Most of the bones of the skull are flat bones, as is the sternum.[29]
• Sesamoid bones are bones embedded in tendons. Since they act to hold the tendon further away from the joint, the angle of the tendon is increased and thus the leverage of the muscle is increased. Examples of sesamoid bones are the patella and the pisiform.[30]
• Irregular bones do not fit into the above categories. They consist of thin layers of compact bone surrounding a spongy interior. As implied by the name, their shapes are irregular and complicated. Often this irregular shape is due to their many centers of ossification or because they contain bony sinuses. The bones of the spine, pelvis, and some bones of the skull are irregular bones. Examples include the ethmoid and sphenoid bones.[31]

In the study of anatomy, anatomists use a number of anatomical terms to describe the appearance, shape and function of bones. Other anatomical terms are also used to describe the location of bones. Like other anatomical terms, many of these derive from Latin and Greek. Some anatomists still use Latin to refer to bones. The term "osseous", and the prefix "osteo-", referring to things related to bone, are still used commonly today.

Some examples of terms used to describe bones include the term "foramen" to describe a hole through which something passes, and a "canal" or "meatus" to describe a tunnel-like structure. A protrusion from a bone can be called a number of terms, including a "condyle", "crest", "spine", "eminence", "tubercle" or "tuberosity", depending on the protrusion's shape and location. In general, long bones are said to have a "head", "neck", and "body".

When two bones join together, they are said to "articulate". If the two bones have a fibrous connection and are relatively immobile, then the joint is called a "suture".

Bones serve a variety of mechanical functions. Together the bones in the body form the skeleton. They provide a frame to keep the body supported, and an attachment point for skeletal muscles, tendons, ligaments and joints, which function together to generate and transfer forces so that individual body parts or the whole body can be manipulated in three-dimensional space (the interaction between bone and muscle is studied in biomechanics).

Bones protect internal organs, such as the skull protecting the brain or the ribs protecting the heart and lungs. Because of the way that bone is formed, bone has a high compressive strength of about 170 MPa (1,700 kgf/cm²),[5] poor tensile strength of 104–121 MPa, and a very low shear stress strength (51.6 MPa).[38][39] This means that bone resists pushing (compressional) stress well, resist pulling (tensional) stress less well, but only poorly resists shear stress (such as due to torsional loads). While bone is essentially brittle, bone does have a significant degree of elasticity, contributed chiefly by collagen.

Mechanically, bones also have a special role in hearing. The ossicles are three small bones in the middle ear which are involved in sound transduction.

The cancellous part of bones contain bone marrow. Bone marrow produces blood cells in a process called hematopoiesis.[40] Blood cells that are created in bone marrow include red blood cells, platelets and white blood cells.[41] Progenitor cells such as the hematopoietic stem cell divide in a process called mitosis to produce precursor cells. These include precursors which eventually give rise to white blood cells, and erythroblasts which give rise to red blood cells.[42] Unlike red and white blood cells, created by mitosis, platelets are shed from very large cells called megakaryocytes.[43] This process of progressive differentiation occurs within the bone marrow. After the cells are matured, they enter the circulation.[44] Every day, over 2.5 billion red blood cells and platelets, and 50–100 billion granulocytes are produced in this way.[14]

As well as creating cells, bone marrow is also one of the major sites where defective or aged red blood cells are destroyed.[14]

• Mineral storage – bones act as reserves of minerals important for the body, most notably calcium and phosphorus.[45][46]

Determined by the species, age, and the type of bone, bone cells make up to 15 percent of the bone. Growth factor storage—mineralized bone matrix stores important growth factors such as insulin-like growth factors, transforming growth factor, bone morphogenetic proteins and others.[47]

• Fat storage – marrow adipose tissue (MAT) acts as a storage reserve of fatty acids.[48]
• Acid-base balance – bone buffers the blood against excessive pH changes by absorbing or releasing alkaline salts.[49]
• Detoxification – bone tissues can also store heavy metals and other foreign elements, removing them from the blood and reducing their effects on other tissues. These can later be gradually released for excretion.[50]
• Endocrine organ – bone controls phosphate metabolism by releasing fibroblast growth factor 23 (FGF-23), which acts on kidneys to reduce phosphate reabsorption. Bone cells also release a hormone called osteocalcin, which contributes to the regulation of blood sugar (glucose) and fat deposition. Osteocalcin increases both the insulin secretion and sensitivity, in addition to boosting the number of insulin-producing cells and reducing stores of fat.[51]
• Calcium balance – the process of bone resorption by the osteoclasts releases stored calcium into the systemic circulation and is an important process in regulating calcium balance. As bone formation actively fixes circulating calcium in its mineral form, removing it from the bloodstream, resorption actively unfixes it thereby increasing circulating calcium levels. These processes occur in tandem at site-specific locations.[52]

Bone is constantly being created and replaced in a process known as remodeling. This ongoing turnover of bone is a process of resorption followed by replacement of bone with little change in shape. This is accomplished through osteoblasts and osteoclasts. Cells are stimulated by a variety of signals, and together referred to as a remodeling unit. Approximately 10% of the skeletal mass of an adult is remodelled each year.[53] The purpose of remodeling is to regulate calcium homeostasis, repair microdamaged bones from everyday stress, and to shape the skeleton during growth.[54] Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of maximum stress (Wolff's law). It has been hypothesized that this is a result of bone's piezoelectric properties, which cause bone to generate small electrical potentials under stress.[55]

The action of osteoblasts and osteoclasts are controlled by a number of chemical enzymes that either promote or inhibit the activity of the bone remodeling cells, controlling the rate at which bone is made, destroyed, or changed in shape. The cells also use paracrine signalling to control the activity of each other.[56][57] For example, the rate at which osteoclasts resorb bone is inhibited by calcitonin and osteoprotegerin. Calcitonin is produced by parafollicular cells in the thyroid gland, and can bind to receptors on osteoclasts to directly inhibit osteoclast activity. Osteoprotegerin is secreted by osteoblasts and is able to bind RANK-L, inhibiting osteoclast stimulation.[58]

Osteoblasts can also be stimulated to increase bone mass through increased secretion of osteoid and by inhibiting the ability of osteoclasts to break down osseous tissue. Increased secretion of osteoid is stimulated by the secretion of growth hormone by the pituitary, thyroid hormone and the sex hormones (estrogens and androgens). These hormones also promote increased secretion of osteoprotegerin.[58] Osteoblasts can also be induced to secrete a number of cytokines that promote reabsorption of bone by stimulating osteoclast activity and differentiation from progenitor cells. Vitamin D, parathyroid hormone and stimulation from osteocytes induce osteoblasts to increase secretion of RANK-ligand and interleukin 6, which cytokines then stimulate increased reabsorption of bone by osteoclasts. These same compounds also increase secretion of macrophage colony-stimulating factor by osteoblasts, which promotes the differentiation of progenitor cells into osteoclasts, and decrease secretion of osteoprotegerin.

Bone volume is determined by the rates of bone formation and bone resorption. Recent research has suggested that certain growth factors may work to locally alter bone formation by increasing osteoblast activity. Numerous bone-derived growth factors have been isolated and classified via bone cultures. These factors include insulin-like growth factors I and II, transforming growth factor-beta, fibroblast growth factor, platelet-derived growth factor, and bone morphogenetic proteins.[59] Evidence suggests that bone cells produce growth factors for extracellular storage in the bone matrix. The release of these growth factors from the bone matrix could cause the proliferation of osteoblast precursors. Essentially, bone growth factors may act as potential determinants of local bone formation.[59] Research has suggested that cancellous bone volume in postmenopausal osteoporosis may be determined by the relationship between the total bone forming surface and the percent of surface resorption.[60]

Radiography used to identify possible bone fractures after a knee injury

In normal bone, fractures occur when there is significant force applied, or repetitive trauma over a long time. Fractures can also occur when a bone is weakened, such as with osteoporosis, or when there is a structural problem, such as when the bone remodels excessively (such as Paget's disease) or is the site of the growth of cancer.[62] Common fractures include wrist fractures and hip fractures, associated with osteoporosis, vertebral fractures associated with high-energy trauma and cancer, and fractures of long-bones. Not all fractures are painful.[62] When serious, depending on the fractures type and location, complications may include flail chest, compartment syndromes or fat embolism. Compound fractures involve the bone's penetration through the skin. Some complex fractures can be treated by the use of bone grafting procedures that replace missing bone portions.

Fractures and their underlying causes can be investigated by X-rays, CT scans and MRIs.[62] Fractures are described by their location and shape, and several classification systems exist, depending on the location of the fracture. A common long bone fracture in children is a Salter–Harris fracture.[63] When fractures are managed, pain relief is often given, and the fractured area is often immobilised. This is to promote bone healing. In addition, surgical measures such as internal fixation may be used. Because of the immobilisation, people with fractures are often advised to undergo rehabilitation.[62]

There are several types of tumour that can affect bone; examples of benign bone tumours include osteoma, osteoid osteoma, osteochondroma, osteoblastoma, enchondroma, giant cell tumour of bone, and aneurysmal bone cyst.[64]

Cancer can arise in bone tissue, and bones are also a common site for other cancers to spread (metastasise) to.[65] Cancers that arise in bone are called "primary" cancers, although such cancers are rare.[65] Metastases within bone are "secondary" cancers, with the most common being breast cancer, lung cancer, prostate cancer, thyroid cancer, and kidney cancer.[65] Secondary cancers that affect bone can either destroy bone (called a "lytic" cancer) or create bone (a "sclerotic" cancer). Cancers of the bone marrow inside the bone can also affect bone tissue, examples including leukemia and multiple myeloma. Bone may also be affected by cancers in other parts of the body. Cancers in other parts of the body may release parathyroid hormone or parathyroid hormone-related peptide. This increases bone reabsorption, and can lead to bone fractures.

Bone tissue that is destroyed or altered as a result of cancers is distorted, weakened, and more prone to fracture. This may lead to compression of the spinal cord, destruction of the marrow resulting in bruising, bleeding and immunosuppression, and is one cause of bone pain. If the cancer is metastatic, then there might be other symptoms depending on the site of the original cancer. Some bone cancers can also be felt.

Cancers of the bone are managed according to their type, their stage, prognosis, and what symptoms they cause. Many primary cancers of bone are treated with radiotherapy. Cancers of bone marrow may be treated with chemotherapy, and other forms of targeted therapy such as immunotherapy may be used.[66] Palliative care, which focuses on maximising a person's quality of life, may play a role in management, particularly if the likelihood of survival within five years is poor.

• Osteomyelitis is inflammation of the bone or bone marrow due to bacterial infection.
• Osteomalacia is a painful softening of adult bone caused by severe vitamin D deficiency.
• Osteogenesis imperfecta
• Osteochondritis dissecans
• Ankylosing spondylitis
• Skeletal fluorosis is a bone disease caused by an excessive accumulation of fluoride in the bones. In advanced cases, skeletal fluorosis damages bones and joints and is painful.

Reduced bone mineral density in Osteoporosis (R), increasing the likelihood of fractures

Osteoporosis is a disease of bone where there is reduced bone mineral density, increasing the likelihood of fractures.[67] Osteoporosis is defined in women by the World Health Organization as a bone mineral density of 2.5 standard deviations below peak bone mass, relative to the age and sex-matched average. This density is measured using dual energy X-ray absorptiometry (DEXA), with the term "established osteoporosis" including the presence of a fragility fracture.[68] Osteoporosis is most common in women after menopause, when it is called "postmenopausal osteoporosis", but may develop in men and premenopausal women in the presence of particular hormonal disorders and other chronic diseases or as a result of smoking and medications, specifically glucocorticoids.[67] Osteoporosis usually has no symptoms until a fracture occurs.[67] For this reason, DEXA scans are often done in people with one or more risk factors, who have developed osteoporosis and are at risk of fracture.[67]

Osteoporosis treatment includes advice to stop smoking, decrease alcohol consumption, exercise regularly, and have a healthy diet. Calcium and trace mineral supplements may also be advised, as may Vitamin D. When medication is used, it may include bisphosphonates, Strontium ranelate, and hormone replacement therapy.[69]

Osteopathic medicine is a school of medical thought originally developed based on the idea of the link between the musculoskeletal system and overall health, but now very similar to mainstream medicine. As of 2012, over 77,000 physicians in the United States are trained in osteopathic medical schools.[70]