Macroscopic bone structure

Macroscopic bone structure DEFAULT

Anatomy and Ultrastructure of Bone – Histogenesis, Growth and Remodeling


Bones have three major functions: to serve as mechanical support, sites of muscle insertion and as a reserve of calcium and phosphate for the organism. Recently, a fourth function has been attributed to the skeleton: an endocrine organ. The organic matrix of bone is formed mostly of collagen, but also non-collagenous proteins. Hydroxyapatite crystals bind to both types of proteins. Most components of the bone matrix are synthesized and secreted by osteoblasts. Resorption of the bone matrix is required for adaptation to growth, repair and mineral mobilization. This process is performed by the macrophage-related osteoclast. Bone is remodeled throughout life through a coordinated sequence of events which involve the sequential actions of osteoclasts and osteoblasts, replacing old bone with new bone. In the normal adult skeleton, remodeling is coupled such that the level of resorption is equal to the level of formation and bone density remains constant. Intramembranous ossification is the process by which flat bones are formed. For this process, osteoblasts differentiate directly from mesenchymal cells to form the bone matrix. Long bones are formed by endochondral ossification, which is characterized by the presence of a cartilaginous model in which chondrocytes differentiate and mineralized cartilage is replaced with bone through remodeling. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.


Bone, a specialized and mineralized connective tissue, makes up, with cartilage, the skeletal system, which serves three main functions: A mechanical function as support and site of muscle attachment for locomotion; a protective function for vital organs and bone marrow; and finally a metabolic function as a reserve of calcium and phosphate used for the maintenance of serum homeostasis, which is essential to life. Recently, a fourth important function has been attributed to bone tissue – that of an endocrine organ. Bone cells produce fibroblast growth factor 23 (FGF23) and osteocalcin. FGF23 regulates phosphate handling in the kidney and osteocalcin regulates energy and glucose metabolism (see below) (1,2).

In this chapter the anatomy and cell biology of bone is described as well as the mechanisms of bone remodeling, development, and growth. Remodeling is the process by which bone is turned-over, allowing the maintenance of the shape, quality, and amount of the skeleton. This process is characterized by the coordinated actions of osteoclasts and osteoblasts, organized in bone multicellular units (BMUs) which follow an Activation-Resorption-Formation sequence of events. During embryonic development, bone formation occurs by two different means: intramembranous ossification and endochondral ossification. Bone Growth is a term used to describe the changes in bone structure once the skeleton is formed and during the period of skeletal growth and maturation.


Two types of bones are found in the skeleton: flat bones (skull bones, scapula, mandible, and ileum) and long bones (tibia, femur, humerus, etc.). These are derived by two distinct types of development: intramembranous and endochondral, respectively, although the development and growth of long bones actually involve both cellular processes. The main difference between intramembranous and endochondral bone formation is the presence of a cartilaginous model, or anlage, in the latter.

Long bones have two wider extremities (the epiphyses), a cylindrical hollow portion in the middle (the midshaft or diaphysis), and a transition zone between them (the metaphysis). The epiphysis on the one hand and the metaphysis and midshaft on the other hand originate from two independent ossification centers, and are separated by a layer of cartilage, the epiphyseal cartilage (which also constitutes the growth plate) during the period of development and growth. This layer of proliferative cells and expanding cartilage matrix is responsible for the longitudinal growth of bones; it progressively mineralizes and is later remodeled and replaced by bone tissue by the end of the growth period (see section on Skeletal Development). The external part of the bones is formed by a thick and dense layer of calcified tissue, the cortex (compact bone) which, in the diaphysis, encloses the medullary cavity where the hematopoietic bone marrow is housed. Toward the metaphysis and the epiphysis, the cortex becomes progressively thinner and the internal space is filled with a network of thin, calcified trabeculae forming the cancellous or trabecular bone. The spaces enclosed by these thin trabeculae are also filled with hematopoietic bone marrow and are continuous with the diaphyseal medullary cavity. The outer cortical bone surfaces at the epiphyses are covered with a layer of articular cartilage that does not calcify.

Bone is consequently in contact with the soft tissues along two surfaces: an external surface (the periosteal surface) and an internal surface (the endosteal surface). These surfaces are lined with osteogenic cells along the periosteum and the endosteum, respectively.

Cortical and trabecular bone are made up of the same cells and the same matrix elements, but there are structural and functional differences. The primary structural difference is quantitative: 80% to 90% of the volume of compact bone is calcified, whereas only 15% to 25% of the trabecular volume is calcified (the remainder being occupied by bone marrow, blood vessels, and connective tissue). The result is that 70% to 85% of the interface with soft tissues is at the endosteal bone surface, including all trabecular surfaces, leading to the functional difference: the cortical bone fulfills mainly a mechanical and protective function and the trabecular bone mainly a metabolic function, albeit trabeculae definitively participate in the biomechanical function of bones, particularly in bones like the vertebrae.

Recently, more attention has been given to cortical bone structure since cortical porosity is intimately linked to the remodeling process as well as to bone strength. Indeed, an increase in cortical porosity is associated with an increase in fragility fractures (3).


Bone matrix consists mainly of type I collagen fibers (approximately 90%) and non-collagenous proteins. Within lamellar bone, the fibers are forming arches for optimal bone strength. This fiber organization allows the highest density of collagen per unit volume of tissue. The lamellae can be parallel to each other if deposited along a flat surface (trabecular bone and periosteum), or concentric if deposited on a surface surrounding a channel centered on a blood vessel (cortical bone Haversian system). Spindle- or plate-shaped crystals of hydroxyapatite [3Ca 3 (PO 42 ·(OH) 2] are found on the collagen fibers, within them, and in the matrix around. They tend to be oriented in the same direction as the collagen fibers.

When bone is formed very rapidly during development and fracture healing, or in tumors and some metabolic bone diseases, there is no preferential organization of the collagen fibers. They are then not as tightly packed and found in somewhat randomly oriented bundles: this type of bone is called woven bone, as opposed to lamellar bone. Woven bone is characterized by irregular bundles of collagen fibers, large and numerous osteocytes, and delayed, disorderly calcification which occurs in irregularly distributed patches. Woven bone is progressively replaced by mature lamellar bone during the remodeling process that follows normally development or healing (see below).

Numerous non-collagenous proteins present in bone matrix have been purified and sequenced, but their role has been only partially characterized (Table 1) (4). Most non-collagenous proteins within the bone matrix are synthesized by osteoblasts, but not all: approximately a quarter of the bone non-collagenous proteins are plasma proteins which are preferentially absorbed by the bone matrix, such as a 2-HS-glycoprotein, which is synthesized in the liver. The major non-collagenous protein produced is osteocalcin, which makes up 1% of the matrix, and may play a role in calcium binding and stabilization of hydroxyapatite in the matrix and/or regulation of bone formation, as suggested by increased bone mass in osteocalcin knockout mice. Another negative regulator of bone formation found in the matrix is matrix gla protein, which appears to inhibit premature or inappropriate mineralization, as demonstrated in a knockout mouse model. In contrast to this, biglycan, a proteoglycan, is expressed in the bone matrix, and positively regulates bone formation, as demonstrated by reduced bone formation and bone mass in biglycan knockout mice. Osteocalcin has recently been shown to have an important endocrine function acting on the pancreatic beta cell. Its hormonally active form (undercarboxylated osteocalcin, stimulates insulin secretion and enhances insulin sensitivity in adipose tissues and muscle, improving glucose utilization in peripheral tissues (2).

Table 1.

Non-collagenous Proteins in Bone (4)

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Osteonectin (SPARC)32KCalcium, apatite and matrix protein binding
Modulates cell attachment
α-2-HS-Glycoprotein46-67KChemotactic for monocytes
Mineralization via matrix vesicles
Osteocalcin (Bone GLA protein)6KInvolved in stabilization of hydroxyapatite
Binding of calcium
Chemotactic for monocytes
Regulation of bone formation
Matrix-GLA-protein9KInhibits matrix mineralization
(Bone Sialoprotein I)
50KCell attachment (via RGD sequence)
Calcium binding
Bone Sialoprotein II75KCell attachment (via RGD sequence)
Calcium binding
24K Phosphoprotein
(α-1(I) procollagen N-propeptide)
24KResidue from collagen processing
Biglycan (Proteoglycan I)45K coreRegulation of collagen fiber growth
Mineralization and bone formation
Growth factor binding
Decorin (Proteoglycan II)36K core + side chainsCollagen fibrillogenesis
Growth factor binding
Thrombospondin & FibronectinCell attachment (via RGD sequence)
Growth factor binding
Hydroxyapatite formation
Others (including proteolipidsMineralization
Growth Factors
Bone morphogenetic proteins (BMPs)
Differentiation, proliferation and activity of osteoblasts
Induction of bone and cartilage in osteogenesis and fracture repair


The calcified bone matrix is not metabolically inert, and cells (osteocytes) are found embedded deep within the bone in small lacunae (Figure 1). All osteocytes are derived from bone forming cells (osteoblasts) which have been trapped in the bone matrix that they produced and which became calcified. Even though the metabolic activity of the osteoblast decreases dramatically once it is fully encased in bone matrix, now becoming an osteocyte, these cells still produce matrix proteins.

Figure 1. . Wnt signaling determines the cell fate of mesenchymal progenitor cells and regulates bone formation and resorption.

Figure 1.

Wnt signaling determines the cell fate of mesenchymal progenitor cells and regulates bone formation and resorption. The Wnt canonical pathway represses adipocyte differentiation and chondrocyte differentiation from progenitor cells, whereas it is required for the transition of chondrocytes to hypertrophy. In contrast, Wnt pathway activation promotes the osteoblast cell lineage by controlling proliferation, maturation, terminal differentiation, and bone formation. Differentiated osteoblasts and/or osteocytes produce Wnt inhibitors such as Dickkopf (Dkk1) and sclerostin (Sost) proteins as a negative feedback control of osteoblast differentiation and function. Wnt signaling also induces osteoblasts to produce more osteoprotegerin (OPG), increasing the ratio of OPG to receptor activator of NF-κB ligand (RANKL) to decrease osteoclast differentiation and bone resorption.

Osteocyte morphology varies according to cell age and functional activity. A young osteocyte has most of the ultrastructural characteristics of the osteoblast from which it was derived, except that there has been a decrease in cell volume and in the importance of the organelles involved in protein synthesis (rough endoplasmic reticulum, Golgi). An older osteocyte, located deeper within the calcified bone, shows a further decrease in cell volume and organelles, and an accumulation of glycogen in the cytoplasm. These cells synthesize small amounts of new bone matrix at the surface of the osteocytic lacunae, which can subsequently calcify. Osteocytes express, in low levels, a number of osteoblast markers, including osteocalcin, osteopontin, osteonectin and the osteocyte marker E11.

Osteocytes have numerous long cell processes rich in microfilaments, which are in contact with cell processes from other osteocytes (there are frequent gap junctions), or with processes from the cells lining the bone surface (osteoblasts or flat lining cells). These processes are organized during the formation of the matrix and before its calcification; they form a network of thin canaliculi permeating the entire bone matrix. Osteocytic canaliculi are not distributed evenly around the cell, but are mainly directed toward the bone surface. Between the osteocyte's plasma membrane and the bone matrix itself is the periosteocytic space. This space exists both in the lacunae and in the canaliculi, and it is filled with extracellular fluid (ECF), the only source of nutrients, cytokines and hormones for the osteocyte. ECF flow through the canalicular network is altered during bone matrix compression and tension and is believed not only to allow exchanges with the extracellular fluids in the surrounding tissues but also to create shear forces that are directly involved in mechanosensing and regulation of bone remodeling. Current understanding of mechanotransduction is based upon the presence of a mechanosensing cilium at the level of the osteocyte’s cell body, capable of detecting the changes in fluid flow determined by mechanical loading of bone. In turn, the activation of the mechanosensing cilium may determine the local concentration of cytokines capable of regulating bone formation and/or bone resorption, such as RANKL, OPG or sclerostin (see below).

Indeed, given the structure of the network and the location of osteocytes within lacunae where ECF flow can be detected, it is likely that osteocytes respond to bone tissue strain and influence bone remodeling activity by recruiting osteoclasts to sites where bone remodeling is required. Osteocyte cellular activity is increased after bone loading; studies in cell culture have demonstrated increased calcium influx and prostaglandin production by osteocytes after mechanical stimulation, but there is no direct evidence for osteocytes signaling to cells on the bone surface in response to bone strain or microdamage to date. Osteocytes can become apoptotic and their programmed cell death may be one of the critical signals for induction of bone remodeling. Ultimately, the fate of the osteocyte is to be phagocytosed and digested together with the other components of bone during osteoclastic bone resorption. The recent ability to isolate and culture osteocytes, as well as the creation of immortalized osteocytic cell lines now allows the study of these cells at the molecular level and this is expected to significantly further our understanding of their role in bone biology and disease.(5) In particular, the discoveries that osteocytes can secrete the Wnt antagonist sclerostin and that this secretion is inhibited both by PTH treatment and by mechanical loading establishes the first direct link between biomechanics, endocrine hormones, bone formation and osteocytes. Similarly, osteocytes can secrete RANKL and OPG, contributing also to the regulation of bone resorption. Thus, osteocytes are emerging as the critical cell type linking mechanical forces in bone to the regulation of bone mass and shape through remodeling.


The osteoblast is the bone lining cell responsible for the production of the bone matrix constituents, collagen and non-collagenous proteins (Figure 2). Osteoblasts never appear or function individually but are always found in clusters of cuboidal cells along the bone surface (~100–400 cells per bone-forming site).

Figure 2. . Osteocyte.

Figure 2.

Osteocyte. Electron micrograph of an osteocyte within a lacuna in calcified bone matrix. The cell has a basal nucleus, cytoplasmic extensions, and well-developed Golgi and endoplasmic reticulum.

Osteoblasts do not operate in isolation and gap junctions are often found between osteoblasts working together on the bone surface. Osteoblasts also appear to communicate with the osteocyte network within the bone matrix (see above), since cytoplasmic processes on the secreting side of the osteoblast extend deep into the osteoid matrix and are in contact with processes of the osteocytes dwelling there.

At the light microscope level, the osteoblast is characterized morphologically by a round nucleus at the base of the cell (away from the bone surface), an intensely basophilic cytoplasm, and a prominent Golgi complex located between the nucleus and the apex of the cell. Osteoblasts are always found lining the layer of bone matrix that they are producing, but before it is calcified (osteoid tissue). Osteoid tissue exists because of a time lag of approximately 10 days between matrix formation and its subsequent calcification. Behind the osteoblast can usually be found one or two layers of cells: activated mesenchymal cells and preosteoblasts (see below). A mature osteoblast does not divide.

At the ultrastructural level, the osteoblast is characterized by the presence of a well-developed rough endoplasmic reticulum with dilated cisternae and a dense granular content, and the presence of a large circular Golgi complex comprising multiple Golgi stacks. These organelles are involved in the major activity of the osteoblast: the production and secretion of collagenous and non-collagenous bone matrix proteins, including type I collagen. Osteoblasts also produce a range of growth factors under a variety of stimuli, including the insulin-like growth factors (IGFs), platelet-derived growth factors (PDGFs), basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGFβ), a range of cytokines, the bone morphogenetic proteins (BMPs and Wnts.(3) Osteoblast activity is regulated in an autocrine and paracrine manner by these growth factors, whose receptors can be found on osteoblasts, as well as receptors for a range of endocrine hormones. Classic endocrine receptors include receptors for parathyroid hormone/ parathyroid hormone related protein receptor, thyroid hormone, growth hormone, insulin, progesterone and prolactin. Osteoblastic nuclear steroid hormone receptors include receptors for estrogens, androgens, vitamin D 3 and retinoids. Receptors for paracrine and autocrine effectors include those for epidermal growth factor (EGF), IGFs, PDGF, TGFβ, interleukins, FGFs, BMPs and Wnts (LRP5/6 and Frizzled) (6,7) Osteoblasts also have receptors for several adhesion molecules (integrins) involved in cell attachment to the bone surface.

Among the cytokines secreted by the osteoblast are the main regulators of osteoclast differentiation, i.e. M-CSF, RANKL and osteoprotegerin (OPG) (8,9). M-CSF is essential in inducing the commitment of monocytes to the osteoclast lineage whereas RANKL promotes the differentiation and activity of osteoclasts (see below).

Osteoblasts originate from local pluripotent mesenchymal stem cells, either bone marrow stromal stem cells (endosteum) or connective tissue mesenchymal stem cells (periosteum). These precursors, with the right stimulation, undergo proliferation and differentiate into preosteoblasts, at which point they are committed to differentiate into mature osteoblasts.

The committed preosteoblast is located in apposition to the bone surface, and usually present in layers below active mature osteoblasts. They are elliptical cells, with an elongated nucleus, and are still capable of proliferation. Preosteoblasts lack the well-developed protein synthesizing capability of the mature osteoblast, and do not have the characteristically localized, mature rough endoplasmic reticulum or Golgi apparatus of the mature cell.

The development of the osteoblast phenotype is gradual, with a defined sequence of gene expression and cell activity during development and maturation, controlled by a sequence of transcription factors and cytokines (Figure 3).

Figure 3. . Osteoblasts and Osteoid Tissue.

Figure 3.

Osteoblasts and Osteoid Tissue. A: Light micrograph of a group of osteoblasts producing osteoid; note the newly embedded osteocyte. B: Electron micrograph of 3 osteoblasts covering a layer of mineralizing osteoid tissue. Note the prominent Golgi and endoplasmic reticulum characteristic of active osteoblasts. The black clusters in the osteoid tissue are deposits of mineral. C: Osteoblast Lineage. Osteoblasts originate from undifferentiated mesenchymal cells which are capable of proliferation and which may differentiate into one of a range of cell types. The preosteoblast is also capable of proliferation and may be already committed to an osteoblast phenotype. The mature osteoblast no longer proliferates, but can differentiate further into an osteocyte once embedded in the bone matrix, or to a lining cell on the bone surface.

Two transcription factors, Runx2 and Osterix (Osx), which is downstream of Runx2, are absolutely required for osteoblast differentiation. Runx2 is expressed in mesenchymal condensations and chondrocytes, in addition to osteoblasts. Runx2 target genes include several genes expressed by the mature osteoblast including osteocalcin, bone sialoprotein, osteopontin and collagen a1(I), as well as the Runx2 gene itself. Osx may be mostly important for pushing precursors cells away from the chondrocyte and into the osteoblast lineage.

The most important breakthrough in the understanding of the regulation of bone formation in recent years, is the finding of a clear link between LRP5, a co-receptor for Wnts, and bone mass in humans and in mice. Loss of function in LRP5 leads to the Osteoporosis Pseudo-Glioma syndrome (OPPG), with extremely low bone mass, whereas gain of function leads to the High Bone Mass (HBM) phenotype in humans. In addition, deletion mutations in the gene encoding sclerostin (Sost), another endogenous inhibitor of the Wnt pathway, also lead to osteosclerotic phenotypes (Sclerosteosis, Van Buchem syndrome).(7) These findings have opened a whole new field of investigation both in terms of understanding the mechanism that regulate osteoblasts and their bone-matrix secreting activity and in terms of drug discovery in the hope to target one component of the Wnt signaling pathway and thereby increase bone mass in osteoporotic patients. Of note, in 2019, the FDA approved romosozumab, a monoclonal antibody to sclerostin, for the treatment of postmenopausal women with osteoporosis at high risk for fracture.

Toward the end of the matrix secreting period, a further step is involved in osteoblast maturation. Approximately 15% of the mature osteoblasts become encapsulated in the new bone matrix and differentiate into osteocytes. In contrast, some cells remain on the bone surface, becoming flat lining cells.

Mechanism of Bone Formation

Bone formation occurs by three coordinated processes: the production of osteoid matrix, its maturation, and the subsequent mineralization of the matrix. In normal adult bone, these processes occur at the same rate, so that the balance between matrix production and mineralization is equal. Initially, osteoblasts deposit collagen rapidly, without mineralization, producing a thickening osteoid seam. This is followed by an increase in the mineralization rate to equal the rate of collagen synthesis. In the final stage, the rate of collagen synthesis decreases, and mineralization continues until the osteoid seam is fully mineralized. This time lag (termed the mineralization lag time or osteoid maturation period) appears to be required for osteoid to be modified so it is able to support mineralization. While this delay is not yet understood, it is likely that either collagen cross-linking occurs or an inhibitor of mineralization, such as matrix gla protein, is removed during this time, thus allowing mineralization to proceed.

To initiate mineralization in woven bone, or in growth plate cartilage, high local concentrations of Ca2+ and PO43- ions must be reached in order to induce their precipitation into amorphous calcium phosphate, leading to hydroxyapatite crystal formation. This is achieved by membrane-bound matrix vesicles, which originate by budding from the cytoplasmic processes of the chondrocyte or the osteoblast and are deposited within the matrix during its formation. In the matrix, these vesicles are the first structure wherein hydroxyapatite crystals are observed. The membranes are very rich in alkaline phosphatases and in acidic phospholipids, which hydrolyze inhibitors of calcification in the matrix including pyrophosphate and ATP allowing condensation of apatite crystals. Once the crystals are in the matrix environment, they will grow in clusters which later coalesce to completely calcify the matrix, filling the spaces between and within the collagen fibers. In adult lamellar bone, matrix vesicles are not present, and mineralization occurs in an orderly manner through progression of the mineralization front into the osteoid tissue.


The osteoclast is the bone lining cell responsible for bone resorption (Figure 4). The osteoclast is a giant multinucleated cell, up to 100mm in diameter and containing four to 20 nuclei. It is usually found in contact with a calcified bone surface and within a lacuna (Howship's lacunae) that is the result of its own resorptive activity. It is possible to find up to four or five osteoclasts in the same resorptive site, but there are usually only one or two. Under the light microscope, the nuclei appear to vary within the same cell: some are round and euchromatic, and some are irregular in contour and heterochromatic, possibly reflecting asynchronous fusion of mononuclear precursors. The cytoplasm is "foamy" with many vacuoles. The zone of contact with the bone is characterized by the presence of a ruffled border with dense patches on each side (the sealing zone).

Figure 4. . Osteoclasts and the Mechanism of Bone Resorption.

Figure 4.

Osteoclasts and the Mechanism of Bone Resorption. A: Light micrograph and B: electron micrograph of an osteoclast, demonstrating the ruffled border and numerous nuclei. C: Osteoclastic resorption. The osteoclast forms a sealing zone via integrin mediated attachment to specific peptide sequences within the bone matrix, forming a sealed compartment between the cell and the bone surface. This compartment is acidified such that an optimal pH is reached for lysosomal enzyme activity and bone resorption.

Characteristic ultrastructural features of this cell are abundant Golgi complexes around each nucleus, mitochondria, and transport vesicles loaded with lysosomal enzymes. The most prominent features of the osteoclast are, however, the deep foldings of the plasma membrane in the area facing the bone matrix (ruffled border) and the surrounding zone of attachment (sealing zone). The sealing zone is formed by a ring of focal points of adhesion (podosomes) with a core of actin and several cytoskeletal and regulatory proteins around it, that attach the cell to the bone surface, thus sealing off the subosteoclastic bone-resorbing compartment. The attachment of the cell to the matrix is performed via integrin receptors, which bind to specific RGD (Arginine-Glycine-Aspartate) sequences found in matrix proteins (see Table 1). The plasma membrane in the ruffled border area contains proteins that are also found at the limiting membrane of lysosomes and related organelles, and a specific type of electrogenic vacuolar proton ATPase involved in acidification. The basolateral plasma membrane of the osteoclast is specifically enriched in Na+, K+-ATPase (sodium pumps), HCO 3 - /Cl -exchangers, and Na+/H+ exchangers and numerous ion channels (10).

Lysosomal enzymes such as tartrate resistant acid phosphatase and cathepsin K are actively synthesized by the osteoclast and are found in the endoplasmic reticulum, Golgi, and many transport vesicles. The enzymes are secreted, via the ruffled border, into the extracellular bone-resorbing compartment where they reach a sufficiently high extracellular concentration because this compartment is sealed off. The transport and targeting of these enzymes for secretion at the apical pole of the osteoclast involves mannose-6-phosphate receptors. Furthermore, the cell secretes several metalloproteinases such as collagenase (MMP-13) and gelatinase B (MMP-9) which appear to be involved in preosteoclast migration to the bone surface as well as bone matrix digestion. Among the key enzymes being synthesized and secreted by the osteoclast is cathepsin K, an enzyme capable or degrading collagen at low pH and a target for inhibition of bone resorption. (11)

Attachment of the osteoclast to the bone surface is essential for bone resorption. This process involves transmembrane adhesion receptors of the integrin. Integrins attach to specific amino acid sequences (mostly RGD sequences) within proteins in or at the surface of the bone matrix. In the osteoclast, αvβ3 (vitronectin receptor), α2β1 (collagen receptor) and αvβ5 integrins are predominantly expressed. Without cell attachment the acidified microenvironment cannot be established and the osteoclast cannot be highly mobile, a functional property associated with the formation of podosomes.

After osteoclast adhesion to the bone matrix, αvβ3 binding activates cytoskeletal reorganization within the osteoclast, including cell spreading and polarization. In most cells, cell attachment occurs via focal adhesions, where stress fibers (bundles of microfilaments) anchor the cell to the substrate. In osteoclasts, attachment occurs via podosomes. Podosomes are more dynamic structures than focal adhesions, and occur in cells that are highly motile. It is the continual assembly and disassembly of podosomes that allows osteoclast movement across the bone surface during bone resorption. Integrin signaling and subsequent podosome formation is dependent on a number of adhesion kinases including the proto-oncogene src, which, while not required for osteoclast maturation, is required for osteoclast function, as demonstrated by osteopetrosis in the src knockout mouse. Pyk2, another member of the focal adhesion kinase family is also activated by αvβ3 during osteoclast attachment, and is required for bone resorption.(10) Several actin-regulatory proteins have also been shown to be present in podosomes and required for bone resorption, again pointing to the importance of integrin signaling and podosome assembly and disassembly in the function of osteoclasts. (12)

Osteoclasts resorb bone by acidification and proteolysis of the bone matrix and hydroxyapatite crystals encapsulated within the sealing zone. Carbonic anhydrase type II produces hydrogen ions within the cell, which are then pumped across the ruffled border membrane via proton pumps located in the basolateral membrane, thereby acidifying the extracellular compartment. The protons are highly concentrated in the cytosol of the osteoclast; ATP and CO2 are provided by the mitochondria. The basolateral membrane activity exchanges bicarbonate for chloride, thereby avoiding alkalization of the cytosol. K+ channels in the basolateral domain and Cl - channels in the apical ruffled border ensure dissipation of the electrogenic gradients generated by the vacuolar H+-ATPase The basolateral sodium pumps might be involved in secondary active transport of calcium and/or protons in association with a Na + /Ca 2+ exchanger and/or a Na+/H+ antiport. Genetic mutations in several of these components of the acidification and ion transport systems have been shown to be associated with osteopetrosis (defective bone resorption by osteoclasts) in humans and in mice.

The first process during bone matrix resorption is mobilization of the hydroxyapatite crystals by digestion of their link to collagen via the non-collagenous proteins and the low pH dissolves the hydroxyapatite crystals, exposing the bone matrix. Then the residual collagen fibers are digested by cathepsin K, now at optimal pH. The residues from this extracellular digestion are either internalized, or transported across the cell and released at the basolateral domain. Residues may also be released during periods of sealing zone relapse, as probably occurs during osteoclast motility, and possibly induced by a calcium sensor responding to the rise of extracellular calcium in the bone-resorbing compartment.

The regulation of bone resorption is mostly mediated by the action of hormones on stromal cells, osteoblasts and osteocytes. For example, PTH can stimulate osteoblastic production of M-CSF, RANKL, OPG or IL-6, which then act directly on the osteoclast (5,6).

Origin and Fate of the Osteoclast (6)

The osteoclast derives from cells in the mononuclear phagocyte lineage (Figure 5). Their differentiation requires the transcription factors PU-1 and MiTf at early stages, committing the precursors into the myeloid lineage. M-CSF is then required to engage the cells in the monocyte lineage and ensure their proliferation and the expression of the RANK receptor. At that stage, the cells require the presence of RANKL, a member of the TNF family of cytokines produced by stromal cells, to truly commit to the osteoclast lineage and progress in their differentiation program. This step also requires expression of TRAF6, NFκB, c-Fos and NFAT c1, all downstream effectors of RANK signaling. Although this differentiation occurs at the early promonocyte stage, monocytes and macrophages already committed to their own lineage might still be able to form osteoclasts under the right stimuli. Despite its mononuclear phagocytic origin, the osteoclast membrane express distinct markers: it is devoid of Fc and C 3 receptors, as well as of several other macrophage markers; like mononuclear phagocytes, however, the osteoclast is rich in nonspecific esterases, synthesizes lysozyme, and expresses CSF-1 receptors. Monoclonal antibodies have been produced that recognize osteoclasts but not macrophages. The osteoclast, unlike macrophages, also expresses, millions of copies of the RANK, calcitonin, and vitronectin (integrin αvβ3) receptors. Whether it expresses receptors for parathyroid hormone, estrogen, or vitamin D is still controversial. Dendritic cell-specific transmembrane protein (DC-STAMP) is currently considered to be the master regulator of osteoclastogenesis. Knock out of DC-STAMP completely abrogates cell-cell fusion during osteoclastogenesis; osteoclasts isolated from DC-STAMP knock-out mice are mononucleated. (13) Another important factor involved in cell fusion is Pin 1, an enzyme that specifically recognizes the peptide bond between phosphorylated serine or threonine and proline. Pin 1 regulates cell fusion during osteoclastogeneis by suppressing DC-STAMP. (14,15) Recent evidence suggest that the osteoclast undergoes apoptosis after a cycle of resorption, a process favored by estrogens, possibly explaining the increased bone resorption after gonadectomy or menopause.

Figure 5. . Osteoclast Life Cycle.

Figure 5.

Osteoclast Life Cycle. The osteoclast is derived from a mononuclear hematopoietic precursor cell which, upon activation, fuses with other precursors to form a multinucleated osteoclast. The osteoclast first attaches to the bone surface then commences resorption. After a cycle of bone resorption, the osteoclast undergoes apoptosis.

Relations to the Immune System (Osteoimmunology)

In the last few years it has been recognized that, in part due to the link between the osteoclast, macrophages and dendritic cells (all three belong to the same cell lineage), osteoclasts are regulated by and share regulatory mechanisms with cells of the immune system. For instance, T cells can produce locally RANKL, activating osteoclastogenesis. B cells may share a common precursor with and regulate osteoclast precursors. RANKL signaling and “immunoreceptor tyrosine-based activation motif” (ITAM) signals cooperate in osteoclastogenesis (16).


Bone remodeling is the process by which bone is turned over; it is the result of the activity of the bone cells at the surfaces of bone, mainly the endosteal surface (which includes all trabecular surfaces). Remodeling is traditionally classified into two distinct types: Haversian remodeling within the cortical bone and endosteal remodeling along the trabecular bone surface. This distinction is more morphological than physiological because the Haversian surface is an extension of the endosteal surface and the cellular events during these two remodeling processes follow exactly the same sequence.

The Remodeling Sequence

Bone formation and bone resorption do not occur along the bone surface at random: they are coordinated as part of the turnover mechanism by which old bone is replaced by new bone, providing an opportunity to change the shape, architecture or density of the skeleton. In the normal adult skeleton, bone formation only occurs, for the most part, where bone resorption has already occurred. This basic principle of cellular activity at the remodeling site constitutes the Activation-Resorption-Reversal-Formation (ARRF) sequence (Figure 6).

Figure 6. . The Bone Remodeling Sequence.

Figure 6.

The Bone Remodeling Sequence. The Activation-Resorption-Reversal-Formation cycle of bone remodeling as it occurs in trabecular bone. See text for details.

Under some signal, today considered to emanate from osteocytes, a locally acting factor released by lining cells, osteocytes, marrow cells, or in response to bone deformation or fatigue-related microfracture, a group of preosteoclasts are activated. These mononuclear cells attach to the bone via αvβ3 integrins and fuse to form a multi-nucleated osteoclast which will, in a definite area of the bone surface, resorb the bone matrix. After resorption of the bone, and osteoclast detachment, uncharacterized mononuclear cells cover the surface and a cement line is formed. The cement line marks the limit of bone resorption, and acts to cement together the old and the new bone. This is termed the reversal phase, and is followed by a period of bone formation. Preosteoblasts are activated, proliferate and differentiate into osteoblasts, which move onto the bone surface, forming an initial matrix (osteoid), which becomes mineralized after a time lag (the osteoid maturation period). The basic remodeling sequence is therefore Activation-Resorption-Formation; it is performed by a group of cells called the Basic Multicellular Unit (BMU). The complete remodeling cycle takes about 3 months in humans (Figure 7).

Figure 7. . Bone Growth and Remodeling at the Growth Plate.

Figure 7.

Bone Growth and Remodeling at the Growth Plate. The light micrograph demonstrates the zones of chondrocyte differentiation, as well as mineralization (black). The schematic representation shows the cellular events occurring at the growth plate in long bones. Note that bone formation in this process occurs by repeated Activation-Resorption-Formation cycles of bone remodeling beginning with the calcified cartilage matrix.

For decades, the reversal phase of the remodeling cycle was the least well understood. It was recognized that during this phase, the resorption cavity was occupied by mononucleated cells, but the nature of these cells was unknown (17). Recent work by Delaisse and colleagues (18) has definitively identified the reversal cells as belonging to the osteogenic lineage, expressing classic osteoblast markers: Runx2, ALP, and Col3. By applying immunocytochemistry and histomorphometry to femur and fibula samples harvested from teenagers and adults, these investigators have provided a much more complete picture of the temporal sequence of cellular events that occur between the start of resorption and the onset of formation. In order to visualize the entire sequence of events, they analyzed longitudinal sections of evolving Haversian systems. They observed osteoclasts at two distinct locations: at the cutting cone (referred to as primary osteoclasts) and close to the reversal cells (referred to as secondary osteoclasts). The presence of secondary osteoclasts in the reversal phase suggests that bone resorption continues during this phase, which has been renamed the resorption-reversal phase. The authors have concluded that the primary osteoclasts are responsible for drilling the tunnel (initial resorption) and the secondary osteoclasts work to increase its diameter by radial resorption. This radial resorption was shown to be a major contributor to the overall amount of bone resorbed in each BMU. This new and more complete model of the resorption-reversal phase will lead to enhanced understanding of the delicate and all-important balance between resorption and formation (Figure 8).

Figure 8. . Cartoon of a bone remodeling unit in cortical bone, showing the change in the designation of the reversal phase as a result of recent new findings.

Figure 8.

Cartoon of a bone remodeling unit in cortical bone, showing the change in the designation of the reversal phase as a result of recent new findings. IR = initial resorption; RR = radial resorption; Og = osteoprogenitor cell; Oc = osteoclast. (17)

For many years it has been accepted that bone resorption and formation are coupled in the same way that bone matrix formation and calcification are linked. In other words, in the normal adult skeleton, the coupling of bone resorption and formation in remodeling results in equal levels of cellular activity so that bone turnover is balanced: the volume of bone resorbed is equal to the volume formed. This paradigm implies that, for example, a reduction in osteoblast activity would affect a similar reduction in osteoclast activity such that bone volume is maintained. Conversely, an increase in osteoclast activity should be compensated by an increase in osteoblasts and bone formation, resulting in a maintained bone mass with a high turnover, as in hyperparathyroidism for instance. Similarly, decreased osteoclast numbers or bone resorption activity should be associated with a decrease in bone formation, maintaining bone mass but with a decreased turnover rate.

Although this “coupling” may indeed function in most cases, there are multiple examples of dysfunctions, such as in osteoporosis or osteopetrosis for instance. It now appears that the number of osteoclasts rather than their strict activity is a key determinant of subsequent bone formation. This suggests that factors generated locally by the osteoclast, either directly or through resorption of the bone matrix, are capable of stimulating bone formation (19).

Haversian vs Endosteal Bone Remodeling

As previously mentioned, although cortical bone is anatomically different to trabecular bone, its remodeling occurs following the same sequence of events. The major difference is that while the average thickness of a trabecula is 150-200 microns, the average thickness of the cortex is of the order of 1-10 mm. There are no blood vessels in the trabeculae but the bone envelope system and the osteocyte network are able to carry out enough gaseous exchange, being always relatively close to the surface and the highly vascularized marrow. Consequently, bone remodeling in the trabecular bone will take place along the trabecular surface. On the other hand, the cortical bone itself needs to be vascularized. Blood vessels are first embedded during the histogenesis of cortical bone; the blood vessel and the bone which surrounds it is then called a primary osteon. Later, cortical bone remodeling will be initiated either along the surface of these vascular channels, or from the endosteal surface of the cortex. The remodeling process in cortical bone also follows the ARF sequence. Osteoclasts excavate a tunnel, creating a cutting cone. Again, there is a reversal phase, where mononuclear cells attach and lay down a cement line. Osteoblasts are then responsible for closing the cone, leaving a central canal, centered on blood vessels and surrounded by concentric bone lamellae. For mechanical reasons, all these Haversian systems are oriented along the longitudinal axis of the bone.

Bone Turnover and Skeletal Homeostasis

In a normal young adult, about 30% of the total skeletal mass is renewed every year (half-life = 20 months). In each remodeling unit, osteoclastic bone resorption lasts about 3 days, the reversal 14 days, and bone formation 70 days (total = 87 days). The linear bone formation rate is 0.5mm/day. During this process, about 0.01mm of bone is renewed in one given remodeling unit. Theoretically, with balanced matrix deposition and calcification as well as a balance between osteoclast and osteoblast activity, the amount of bone formed in each remodeling unit (and therefore in the total skeleton) equals the amount of bone which was previously resorbed. Thus, the total skeletal mass remains constant. This skeletal homeostasis relies upon a normal remodeling activity. The rate of activation of new remodeling units would then determine only the turnover rate.


Bone development is achieved through the use of two distinct processes, intramembranous and endochondral bone formation. In the first, mesenchymal cells differentiate directly into osteoblasts whereas in the second mesenchymal cells differentiate into chondrocytes and it is only secondarily that osteoblasts appear and form bone around the cartilage model. Through a process that involves bone resorption by osteoclasts, vascular invasion and resorption of calcified cartilage, the cartilage model is progressively replaced by osteoblast-derived bone matrix. Bone is then remodeled through continuous cycles of bone resorption and formation, thereby allowing shape changes and adaptation to the local and systemic environment.

Intramembranous Ossification

During intramembranous ossification, a group of mesenchymal cells within a highly vascularized area of the embryonic connective tissue proliferates, forming early mesenchymal condensations within which cells differentiate directly into osteoblasts. Bone Morphogenetic Proteins, as well as FGFs appear to be essential in the process of mesenchymal cell condensation. The newly differentiated osteoblasts will synthesize a woven bone matrix, while at the periphery, mesenchymal cells continue to differentiate into osteoblasts. Blood vessels are incorporated between the woven bone trabeculae and will form the hematopoietic bone marrow. Later this woven bone will be remodeled through the classical remodeling process, resorbing woven bone and progressively replacing it with mature lamellar bone.

Endochondral Ossification

Development of long bones begins with the formation of a cartilage anlage (model) from a mesenchymal condensation, as in intramembranous ossification. (Figure 9). But here, under the influence of a different set of factors and local conditions, mesenchymal cells undergo division and differentiate into prechondroblasts and then into chondroblasts rather than directly into osteoblasts. These cells secrete the cartilaginous matrix, where the predominant collagen type is collagen type II. Like osteoblasts, the chondroblasts become progressively embedded within their own matrix, where they lie within lacunae, and they are then called chondrocytes. Unlike osteocytes however, chondrocytes continue to proliferate for some time, this being allowed in part by the gel-like consistency of cartilage. At the periphery of this cartilage (the perichondrium), the mesenchymal cells continue to proliferate and differentiate through appositional growth. Another type of growth is observed in the cartilage by cell proliferation and synthesis of new matrix between the chondrocytes (interstitial growth).

Figure 9. . Duration and depth of the phases of the normal cancellous bone remodeling sequence, calculated from histomorphometric analysis of bone biopsy samples from young individuals (Adapted from: Eriksen EF, Axelrod DW, Melsen F.

Figure 9.

Duration and depth of the phases of the normal cancellous bone remodeling sequence, calculated from histomorphometric analysis of bone biopsy samples from young individuals (Adapted from: Eriksen EF, Axelrod DW, Melsen F. Bone Histomorphometry. Raven Press, New York, pp13-20, 1994).

Beginning in the center of the cartilage model, at what is to become the primary ossification center, chondrocytes continue to differentiate and become hypertrophic. During this process, hypertrophic cells deposit a mineralized matrix, where cartilage calcification is initiated by matrix vesicles. Once this matrix is calcified, it is partially resorbed by osteoclasts. After resorption and a reversal phase, osteoblasts differentiate in this area and form a layer of woven bone on top of the remaining cartilage. This woven bone will later be remodeled into lamellar bone.

Chondrocyte differentiation is regulated by a number of factors which have recently been described. The first factor shown to control chondrocyte differentiation was parathyroid hormone related peptide (PTHrP) acting on PTH receptors mostly found in prehypertrophic chondrocytes. This factor prolongs chondrocyte proliferation, and in PTHrP knockout mice, the main phenotype is bone shortening caused by premature chondrocyte hypertrophy. Targeted overexpression of PTHrP results in the opposite phenotype, with prolonged delay in chondrocyte maturation. PTHrP is part of a genetic signaling cascade, where not only is it regulated by factors expressed earlier in chondrocyte differentiation, such as Indian hedgehog (Ihh), but it also regulates chondrocyte differentiation itself, and alters gene expression in more mature chondrocytes. Other factors which regulate chondrocyte differentiation include the FGFs and bone morphogenetic proteins (BMPs). The transcription factors Runx2 and Sox9, together with the Wnt signaling pathway, control the commitment and differentiation within the chondrocytic lineage (20).

The embryonic cartilage is avascular. During its early development, a ring of woven bone is formed, the bone collar, at the periphery by intramembranous ossification in the future midshaft area under the perichondrium (which becomes periosteum). Following calcification of this woven bone, blood vessels, preceded by osteoclasts enter the primary ossification center, penetrate the bone collar and the calcified cartilage, to form the blood supply and allow seeding of the hematopoietic bone marrow. The osteoclast invasion and its concomitant wave of resorbing activity leads to the removal of the calcified cartilage and its replacement by woven bone in the primary spongiosa, as described above.

Secondary ossification centers begin to form at the epiphyseal ends of the cartilaginous model, and by a similar process, trabecular bone and a marrow space are formed. Between the primary and secondary ossification centers, epiphyseal cartilage (growth plates) remain until adulthood. The continued differentiation of chondrocytes, cartilage mineralization and subsequent remodeling cycles allow longitudinal bone growth to occur, such that as new bone is formed the bone will reach its final adult shape. There is, however, a progressive decrease in chondrocyte proliferation so that the growth plate becomes progressively thinner, allowing mineralization and resorption to catch up. It is at this point that the growth plates are completely remodeled and longitudinal growth is arrested.

The growth plate demonstrates, from the epiphyseal area to the diaphyseal area, the different stages of chondrocyte differentiation involved in endochondral bone formation (Figure 10). Firstly, a proliferative zone, where the chondroblasts divide actively, forming isogenous groups, and actively synthesizing the matrix. These cells become progressively larger, enlarging their lacunae in the pre-hypertrophic and hypertrophic zones. Lower in this area, the matrix of the longitudinal cartilage septa selectively calcifies (zone of provisional calcification). The chondrocytes become highly vacuolated and then die through programmed cell death (apoptosis). Once calcified, the cartilage matrix is resorbed, but only partially, by osteoclasts, leaving the calcified longitudinal septae and blood vessels appear in the zone of invasion. After resorption, osteoblasts differentiate and form a layer of woven bone on top of the cartilaginous remnants of the longitudinal septa. Thus, the first remodeling sequence is complete: the cartilage has been remodeled and replaced by woven bone. The resulting trabeculae are called the primary spongiosa. Still lower in the growth plate, this woven bone is subjected to further remodeling (a second ARF sequence) in which the woven bone and the cartilaginous remnants are replaced with lamellar bone, resulting in the mature trabecular bone called secondary spongiosum.

Figure 10. . Bone Development.

Figure 10.

Bone Development. Schematic diagram showing the initial stages of endochondral ossification. Bone development begins with mesenchymal condensation to form a cartilage model of the bone to be formed. Following chondrocyte hypertrophy and cartilage matrix mineralization, osteoclast activity and vascularization result in the formation of the primary, and then secondary ossification centers. In mature adult bones, the growth plate is fully resorbed, so that one marrow cavity extends the full length of the bone. See text for details.


During longitudinal growth, and due to the fact that the midshaft is narrower than the metaphysis, the growth of a long bone progressively destroys the lower part of the metaphysis and transforms it into a diaphysis, a process accomplished by continuous resorption by osteoclasts beneath the periosteum.

In contrast, growth in the diameter of the metaphysis is the result of a deposition of new membranous bone beneath the periosteum that will continue throughout life. In this case, resorption does not immediately precede formation. Recently, more attention has been focusing on this type of bone formation inasmuch as periosteal bone formation seems to respond differently and/or independently from endosteal bone formation activity to different stimuli such as PTH or biomechanical loading. This is particularly important in the context of osteoporosis where it has been demonstrated that growth in diameter in the midshaft is a more important contributor to the decrease in the fracture risk than trabecular bone density and/or cortical thickness.



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6.3 Bone Structure

Learning Objectives

By the end of this section, you will be able to:

Describe the microscopic and gross anatomical structures of bones

  • Identify the gross anatomical features of a bone
  • Describe the histology of bone tissue, including the function of bone cells and matrix
  • Compare and contrast compact and spongy bone
  • Identify the structures that compose compact and spongy bone
  • Describe how bones are nourished and innervated
  • function?

Bone tissue (osseous tissue) differs greatly from other tissues in the body. Bone is hard and many of its functions depend on that characteristic hardness. Later discussions in this chapter will show that bone is also dynamic in that its shape adjusts to accommodate stresses. This section will examine the gross anatomy of bone first and then move on to its histology.

A long bone has two main regions: the diaphysis and the epiphysis (Figure 6.3.1). The diaphysis is the hollow, tubular shaft that runs between the proximal and distal ends of the bone. Inside the diaphysis is the medullary cavity, which is filled with yellow bone marrow in an adult. The outer walls of the diaphysis (cortex, cortical bone) are composed of dense and hard compact bone, a form of osseous tissue.

This illustration depicts an anterior view of the right femur, or thigh bone. The inferior end that connects to the knee is at the bottom of the diagram and the superior end that connects to the hip is at the top of the diagram. The bottom end of the bone contains a smaller lateral bulge and a larger medial bulge. A blue articular cartilage covers the inner half of each bulge as well as the small trench that runs between the bulges. This area of the inferior end of the bone is labeled the distal epiphysis. Above the distal epiphysis is the metaphysis, where the bone tapers from the wide epiphysis into the relatively thin shaft. The entire length of the shaft is the diaphysis. The superior half of the femur is cut away to show its internal contents. The bone is covered with an outer translucent sheet called the periosteum. At the midpoint of the diaphysis, a nutrient artery travels through the periosteum and into the inner layers of the bone. The periosteum surrounds a white cylinder of solid bone labeled compact bone. The cavity at the center of the compact bone is called the medullary cavity. The inner layer of the compact bone that lines the medullary cavity is called the endosteum. Within the diaphysis, the medullary cavity contains a cylinder of yellow bone marrow that is penetrated by the nutrient artery. The superior end of the femur is also connected to the diaphysis by a metaphysis. In this upper metaphysis, the bone gradually widens between the diaphysis and the proximal epiphysis. The proximal epiphysis of the femur is roughly hexagonal in shape. However, the upper right side of the hexagon has a large, protruding knob. The femur connects and rotates within the hip socket at this knob. The knob is covered with a blue colored articular cartilage. The internal anatomy of the upper metaphysis and proximal epiphysis are revealed. The medullary cavity in these regions is filled with the mesh like spongy bone. Red bone marrow occupies the many cavities within the spongy bone. There is a clear, white line separating the spongy bone of the upper metaphysis with that of the proximal epiphysis. This line is labeled the epiphyseal line.

The wider section at each end of the bone is called the epiphysis (plural = epiphyses), which is filled internally with spongy bone, another type of osseous tissue. Red bone marrow fills the spaces between the spongy bone in some long bones. Each epiphysis meets the diaphysis at the metaphysis. During growth, the metaphysis contains the epiphyseal plate, the site of long bone elongation described later in the chapter. When the bone stops growing in early adulthood (approximately 18–21 years), the epiphyseal plate becomes an epiphyseal line seen in the figure.

Lining the inside of the bone adjacent to the medullary cavity is a layer of bone cells called the endosteum (endo- = “inside”; osteo- = “bone”). These bone cells (described later) cause the bone to grow, repair, and remodel throughout life. On the outside of bones there is another layer of cells that grow, repair and remodel bone as well. These cells are part of the outer double layered structure called the periosteum (peri– = “around” or “surrounding”). The cellular layer is adjacent to the cortical bone and is covered by an outer fibrous layer of dense irregular connective tissue (see Figure 6.3.4a). The periosteum also contains blood vessels, nerves, and lymphatic vessels that nourish compact bone. Tendons and ligaments attach to bones at the periosteum. The periosteum covers the entire outer surface except where the epiphyses meet other bones to form joints (Figure 6.3.2). In this region, the epiphyses are covered with articular cartilage, a thin layer of hyaline cartilage that reduces friction and acts as a shock absorber.

The top of this illustration shows an anterior view of the proximal end of the femur. The top image has two zoom in boxes. The left box is situated on the border between the diaphysis and the metaphysis. Its callout magnifies the periosteum on the right side of the femur. The view shows that the periosteum contains an outer fibrous layer composed of yellow fibers. The inner layer of the periosteum is called the cellular layer, which is composed of irregularly shaped cells. The cellular layer gradually shrinks in width as it transitions from the metaphysis to the diaphysis. A small blood vessel runs through both layers and enters the bone. The right zoom in box magnifies the endosteum on the left side of the bone. The box is situated just inferior to the border between the diaphysis and the metaphysic. It calls out the inner edge of the compact bone layer. The magnified view shows concentric circles of dark colored bone matrix. Between the circles are small cavities containing orange, diamond-shaped cells labeled osteocytes. The left edge of the bone matrix is lined with a single layer of flattened cells called the endosteum. There is a large cell, labeled an osteoclast, between two of the endosteum cells. The osteoclast is cutting a depression into the bony matrix under the endosteum. At another part of the endosteum, three smaller osteoblasts are secreting a blue substance that builds up the outermost layer of the bony matrix.

Flat bones, like those of the cranium, consist of a layer of diploë (spongy bone), covered on either side by a layer of compact bone (Figure 6.3.3). The two layers of compact bone and the interior spongy bone work together to protect the internal organs. If the outer layer of a cranial bone fractures, the brain is still protected by the intact inner layer.

Bone MatrixOsseous tissue is a connective tissue and like all connective tissues contains relatively few cells and large amounts of extracellular matrix. By mass, osseous tissue matrix consists of 1/3rd collagen fibers and 2/3rds calcium phosphate salt. The collagen provides a scaffolding surface for inorganic salt crystals to adhere (see Figure 6.3.4a). These salt crystals form when calcium phosphate and calcium carbonate combine to create hydroxyapatite. Hydroxyapatite also incorporates other inorganic salts like magnesium hydroxide, fluoride, and sulfate as it crystallizes, or calcifies, on the collagen fibers. The hydroxyapatite crystals give bones their hardness and strength, while the collagen fibers give them a framework for calcification and gives the bone flexibility so that it can bend without being brittle. For example, if you removed all the organic matrix (collagen) from a bone, it would crumble and shatter readily (see Figure 6.3.4b, upper panel). Conversely, if you remove all the inorganic matrix (minerals) from bone and leave the collagen, the bone becomes overly flexible and cannot bear weight (see Figure 6.3.4b, lower panel).


Bone Cells

Although bone cells compose less than 2% of the bone mass, they are crucial to the function of bones. Four types of cells are found within bone tissue: osteoblasts, osteocytes, osteogenic cells, and osteoclasts (Figure 6.3.5).

The top of this diagram shows the cross section of a generic bone with three zoom in boxes. The first box is on the periosteum. The second box is on the middle of the compact bone layer. The third box is on the inner edge of the compact bone where it transitions into the spongy bone. The callout in the periosteum points to two images. In the first image, four osteoblast cells are sitting end to end on the periosteum. The osteoblasts are roughly square shaped, except for one of the cells which is developing small, finger like projections. The caption says, “Osteoblasts form the matrix of the bone.” The second image called out from the periosteum shows a large, amorphous osteogenic cell sitting on the periosteum. The osteogenic cell is surrounded on both sides by a row of much smaller osteoblasts. The cell is shaped like a mushroom cap and also has finger like projections. The cell is a stem cell that develops into other bone cells. The box in the middle of the compact bone layer is pointing to an osteocyte. The osteocyte is a thin cell, roughly diamond shaped, with many branching, finger-like projections. The osteoctyes maintain bone tissue. The box at the inner edge of the compact bone is pointing to an osteoclast. The osteoclast is a large, round cell with multiple nuclei. It also has rows of fine finger like projections on its lower surface where it is sitting on the compact bone. The osteoclast reabsorbs bone.

The osteoblast is the bone cell responsible for forming new bone and is found in the growing portions of bone, including the endosteum and the cellular layer of the periosteum. Osteoblasts, which do not divide, synthesize and secrete the collagen matrix and other proteins. As the secreted matrix surrounding the osteoblast calcifies, the osteoblast become trapped within it; as a result, it changes in structure and becomes an osteocyte, the primary cell of mature bone and the most common type of bone cell. Each osteocyte is located in a small cavity in the bone tissue called a lacuna (lacunae for plural). Osteocytes maintain the mineral concentration of the matrix via the secretion of enzymes. Like osteoblasts, osteocytes lack mitotic activity. They can communicate with each other and receive nutrients via long cytoplasmic processes that extend through canaliculi (singular = canaliculus), channels within the bone matrix. Osteocytes are connected to one another within the canaliculi via gap junctions.

If osteoblasts and osteocytes are incapable of mitosis, then how are they replenished when old ones die? The answer lies in the properties of a third category of bone cells—the osteogenic (osteoprogenitor) cell. These osteogenic cells are undifferentiated with high mitotic activity and they are the only bone cells that divide. Immature osteogenic cells are found in the cellular layer of the periosteum and the endosteum. They differentiate and develop into osteoblasts.

The dynamic nature of bone means that new tissue is constantly formed, and old, injured, or unnecessary bone is dissolved for repair or for calcium release. The cells responsible for bone resorption, or breakdown, are the osteoclasts. These multinucleated cells originate from monocytes and macrophages, two types of white blood cells, not from osteogenic cells. Osteoclasts are continually breaking down old bone while osteoblasts are continually forming new bone. The ongoing balance between osteoblasts and osteoclasts is responsible for the constant but subtle reshaping of bone. Table 6.3 reviews the bone cells, their functions, and locations.

Bone Cells (Table 6.3)
Cell typeFunctionLocation
Osteogenic cellsDevelop into osteoblastsEndosteum, cellular layer of the periosteum
OsteoblastsBone formationEndosteum, cellular layer of the periosteum, growing portions of bone
OsteocytesMaintain mineral concentration of matrixEntrapped in matrix
OsteoclastsBone resorptionEndosteum, cellular layer of the periosteum, at sites of old, injured, or unneeded bone

Most bones contain compact and spongy osseous tissue, but their distribution and concentration vary based on the bone’s overall function. Although compact and spongy bone are made of the same matrix materials and cells, they are different in how they are organized. Compact bone is dense so that it can withstand compressive forces, while spongy bone (also called cancellous bone) has open spaces and is supportive, but also lightweight and can be readily remodeled to accommodate changing body needs.

Compact Bone

Compact bone is the denser, stronger of the two types of osseous tissue (Figure 6.3.6). It makes up the outer cortex of all bones and is in immediate contact with the periosteum. In long bones, as you move from the outer cortical compact bone to the inner medullary cavity, the bone transitions to spongy bone.

A generic long bone is shown at the top of this illustration. The bone is split in half lengthwise to show its internal anatomy. The outer gray covering of the bone is labeled the periosteum. Within the periosteum is a thin layer of compact bone. The compact bone surrounds a central cavity called the medullary cavity. The medullary cavity is filled with spongy bone at the two epiphyses. A callout box shows that the main image is zooming in on the compact bone on the left side of the bone. On the main image, the periosteum is being peeled back to show its two layers. The outer layer of the periosteum is the outer fibrous layer. This layer has a periosteal artery and a periosteal vein running along its outside edge. The inner layer of the periosteum is labeled the inner osteogenic layer. The compact bone lies to the right of the periosteum and occupies the majority of the main image. Two flat layers of compact bone line the inner surface of the ostegenic periosteum. These sheets of compact bone are called the circumferential lamellae. The majority of the compact bone has lamellae running perpendicular to that of the circumferential lamellae. These concentric lamellae are arranged in a series of concentric tubes. There are small cavities between the layers of concentric lamellae called lacunae. The centermost concentric lamella surrounds a hollow central canal. A blue vein, a red artery, a yellow nerve and a green lymph vessel run vertically through the central canal. A set of concentric lamellae, its associated lacunae and the vessels and nerves of the central canal are collectively called an osteon. The front edge of the diagram shows a longitudinal cross section of one of the osteons. The vessels and nerve are visible running through the center of the osteon throughout its length. In addition, blood vessels can run from the periosteum through the sides of the osteons and connect with the vessels of the central canal. The blood vessels travel through the sides of the osteons via a perforating canal. The open areas between neighboring osteons are also filled with compact bone. This “filler” bone is referred to as the interstitial lamellae. At the far right of the compact bone, the edge of the spongy bone is visible. The spongy bone is a series of crisscrossing bony arches called trabeculae. There are many open spaces between the trabeculae, giving the spongy bone its sponge-like appearance.

If you look at compact bone under the microscope, you will observe a highly organized arrangement of concentric circles that look like tree trunks. Each group of concentric circles (each “tree”) makes up the microscopic structural unit of compact bone called an osteon (this is also called a Haversian system). Each ring of the osteon is made of collagen and calcified matrix and is called a lamella (plural = lamellae). The collagen fibers of adjacent lamallae run at perpendicular angles to each other, allowing osteons to resist twisting forces in multiple directions (see figure 6.34a). Running down the center of each osteon is the central canal, or Haversian canal, which contains blood vessels, nerves, and lymphatic vessels. These vessels and nerves branch off at right angles through a perforating canal, also known as Volkmann’s canals, to extend to the periosteum and endosteum. The endosteum also lines each central canal, allowing osteons to be removed, remodeled and rebuilt over time.

The osteocytes are trapped within their lacuane, found at the borders of adjacent lamellae. As described earlier, canaliculi connect with the canaliculi of other lacunae and eventually with the central canal. This system allows nutrients to be transported to the osteocytes and wastes to be removed from them despite the impervious calcified matrix.

Spongy (Cancellous) Bone

Like compact bone, spongy bone, also known as cancellous bone, contains osteocytes housed in lacunae, but they are not arranged in concentric circles. Instead, the lacunae and osteocytes are found in a lattice-like network of matrix spikes called trabeculae (singular = trabecula) (Figure 6.3.8). The trabeculae are covered by the endosteum, which can readily remodel them. The trabeculae may appear to be a random network, but each trabecula forms along lines of stress to direct forces out to the more solid compact bone providing strength to the bone. Spongy bone provides balance to the dense and heavy compact bone by making bones lighter so that muscles can move them more easily. In addition, the spaces in some spongy bones contain red bone marrow, protected by the trabeculae, where hematopoiesis occurs.

This illustration shows the spongy bone within the proximal epiphysis of the femur in two successively magnified images. The lower-magnification image shows two layers of crisscrossing trabeculae. The surface of each is dotted with small black holes which are the openings of the canaliculi. One of the trabeculae is in a cross section to show its internal layers. The outermost covering of the lamellae is called the endosteum. This endosteum surrounds several layers of concentric lamellae. The higher-magnification image shows the cross section of the trabeculae more clearly. Three concentric lamellae are shown in this view, each possessing perpendicular black lines. These lines are the canaliculi and are oriented on the round lamellae similar to the spokes of a wheel. In between the lamellae are small cavities called lacunae which house cells called osteocytes. In addition, two large osteoclasts are seated on the outer edge of the outermost lamellae. The outermost lamellae are also surrounded by groups of small, white, osteoblasts.

Aging and the…Skeletal System: Paget’s Disease

Paget’s disease usually occurs in adults over age 40. It is a disorder of the bone remodeling process that begins with overactive osteoclasts. This means more bone is resorbed than is laid down. The osteoblasts try to compensate but the new bone they lay down is weak and brittle and therefore prone to fracture.

While some people with Paget’s disease have no symptoms, others experience pain, bone fractures, and bone deformities (Figure 6.3.9). Bones of the pelvis, skull, spine, and legs are the most commonly affected. When occurring in the skull, Paget’s disease can cause headaches and hearing loss.

This illustration shows the normal skeletal structure of the legs from an anterior view. The flesh of the legs and feet are outlined around the skeleton for reference. A second illustration shows the legs of someone with Paget’s disease. The affected person’s left femur is curved outward, causing the left leg to be bowed and shorter than the right leg.

What causes the osteoclasts to become overactive? The answer is still unknown, but hereditary factors seem to play a role. Some scientists believe Paget’s disease is due to an as-yet-unidentified virus.

Paget’s disease is diagnosed via imaging studies and lab tests. X-rays may show bone deformities or areas of bone resorption. Bone scans are also useful. In these studies, a dye containing a radioactive ion is injected into the body. Areas of bone resorption have an affinity for the ion, so they will light up on the scan if the ions are absorbed. In addition, blood levels of an enzyme called alkaline phosphatase are typically elevated in people with Paget’s disease. Bisphosphonates, drugs that decrease the activity of osteoclasts, are often used in the treatment of Paget’s disease.

The spongy bone and medullary cavity receive nourishment from arteries that pass through the compact bone. The arteries enter through the nutrient foramen (plural = foramina), small openings in the diaphysis (Figure 6.3.10). The osteocytes in spongy bone are nourished by blood vessels of the periosteum that penetrate spongy bone and blood that circulates in the marrow cavities. As the blood passes through the marrow cavities, it is collected by veins, which then pass out of the bone through the foramina.

In addition to the blood vessels, nerves follow the same paths into the bone where they tend to concentrate in the more metabolically active regions of the bone. The nerves sense pain, and it appears the nerves also play roles in regulating blood supplies and in bone growth, hence their concentrations in metabolically active sites of the bone.

This illustration shows an anterior view if the right femur. The femur is split in half lengthwise to show its internal anatomy. The outer covering of the femur is labeled the periosteum. Within it is a thin layer of compact bone that surrounds a central cavity called the medullary or marrow cavity. This cavity is filled with spongy bone at both epiphyses. A nutrient artery and vein travels through the periosteum and compact bone at the center of the diaphysis. After entering the bone, the nutrient arteries and veins spread throughout the marrow cavity in both directions. Some of the arteries and veins in the marrow cavity also spread into the spongy bone within the distal and proximal epiphyses. However, additional blood vessels called the metaphyseal arteries and the metaphyseal veins enter into the metaphysis from outside of the bone.

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Watch this video to see the microscopic features of a bone.

Chapter Review

A hollow medullary cavity filled with yellow marrow runs the length of the diaphysis of a long bone. The walls of the diaphysis are compact bone. The epiphyses, which are wider sections at each end of a long bone, are filled with spongy bone and red marrow. The epiphyseal plate, a layer of hyaline cartilage, is replaced by osseous tissue as the organ grows in length. The medullary cavity has a delicate membranous lining called the endosteum. The outer surface of bone, except in regions covered with articular cartilage, is covered with a fibrous membrane called the periosteum. Flat bones consist of two layers of compact bone surrounding a layer of spongy bone. Bone markings depend on the function and location of bones. Articulations are places where two bones meet. Projections stick out from the surface of the bone and provide attachment points for tendons and ligaments. Holes are openings or depressions in the bones.

Bone matrix consists of collagen fibers and organic ground substance, primarily hydroxyapatite formed from calcium salts. Osteogenic cells develop into osteoblasts. Osteoblasts are cells that make new bone. They become osteocytes, the cells of mature bone, when they get trapped in the matrix. Osteoclasts engage in bone resorption. Compact bone is dense and composed of osteons, while spongy bone is less dense and made up of trabeculae. Blood vessels and nerves enter the bone through the nutrient foramina to nourish and innervate bones.

Review Questions








Critical Thinking Questions

1. If the articular cartilage at the end of one of your long bones were to degenerate, what symptoms do you think you would experience? Why?

2. In what ways is the structural makeup of compact and spongy bone well suited to their respective functions?


articular cartilage
thin layer of cartilage covering an epiphysis; reduces friction and acts as a shock absorber
where two bone surfaces meet
(singular = canaliculus) channels within the bone matrix that house one of an osteocyte’s many cytoplasmic extensions that it uses to communicate and receive nutrients
central canal
longitudinal channel in the center of each osteon; contains blood vessels, nerves, and lymphatic vessels; also known as the Haversian canal
compact bone
dense osseous tissue that can withstand compressive forces
tubular shaft that runs between the proximal and distal ends of a long bone
layer of spongy bone, that is sandwiched between two the layers of compact bone found in flat bones
delicate membranous lining of a bone’s medullary cavity
epiphyseal plate
(also, growth plate) sheet of hyaline cartilage in the metaphysis of an immature bone; replaced by bone tissue as the organ grows in length
wide section at each end of a long bone; filled with spongy bone and red marrow
opening or depression in a bone
(singular = lacuna) spaces in a bone that house an osteocyte
medullary cavity
hollow region of the diaphysis; filled with yellow marrow
nutrient foramen
small opening in the middle of the external surface of the diaphysis, through which an artery enters the bone to provide nourishment
cell responsible for forming new bone
cell responsible for resorbing bone
primary cell in mature bone; responsible for maintaining the matrix
osteogenic cell
undifferentiated cell with high mitotic activity; the only bone cells that divide; they differentiate and develop into osteoblasts
(also, Haversian system) basic structural unit of compact bone; made of concentric layers of calcified matrix
perforating canal
(also, Volkmann’s canal) channel that branches off from the central canal and houses vessels and nerves that extend to the periosteum and endosteum
fibrous membrane covering the outer surface of bone and continuous with ligaments
bone markings where part of the surface sticks out above the rest of the surface, where tendons and ligaments attach
spongy bone
(also, cancellous bone) trabeculated osseous tissue that supports shifts in weight distribution
(singular = trabecula) spikes or sections of the lattice-like matrix in spongy bone


Answers for Critical Thinking Questions

  1. If the articular cartilage at the end of one of your long bones were to deteriorate, which is actually what happens in osteoarthritis, you would experience joint pain at the end of that bone and limitation of motion at that joint because there would be no cartilage to reduce friction between adjacent bones and there would be no cartilage to act as a shock absorber.
  2. The densely packed concentric rings of matrix in compact bone are ideal for resisting compressive forces, which is the function of compact bone. The open spaces of the trabeculated network of spongy bone allow spongy bone to support shifts in weight distribution, which is the function of spongy bone.

Define and list examples of bone markings

The surface features of bones vary considerably, depending on the function and location in the body. Table 6.2 describes the bone markings, which are illustrated in (Figure 6.3.4). There are three general classes of bone markings: (1) articulations, (2) projections, and (3) holes. As the name implies, an articulation is where two bone surfaces come together (articulus = “joint”). These surfaces tend to conform to one another, such as one being rounded and the other cupped, to facilitate the function of the articulation. A projection is an area of a bone that projects above the surface of the bone. These are the attachment points for tendons and ligaments. In general, their size and shape is an indication of the forces exerted through the attachment to the bone. A hole is an opening or groove in the bone that allows blood vessels and nerves to enter the bone. As with the other markings, their size and shape reflect the size of the vessels and nerves that penetrate the bone at these points.

Bone Markings (Table 6.2)
ArticulationsWhere two bones meetKnee joint
HeadProminent rounded surfaceHead of femur
FacetFlat surfaceVertebrae
CondyleRounded surfaceOccipital condyles
ProjectionsRaised markingsSpinous process of the vertebrae
ProcessProminence featureTransverse process of vertebra
SpineSharp processIschial spine
TubercleSmall, rounded processTubercle of humerus
TuberosityRough surfaceDeltoid tuberosity
LineSlight, elongated ridgeTemporal lines of the parietal bones
CrestRidgeIliac crest
HolesHoles and depressionsForamen (holes through which blood vessels can pass through)
FossaElongated basinMandibular fossa
FoveaSmall pitFovea capitis on the head of the femur
SulcusGrooveSigmoid sulcus of the temporal bones
CanalPassage in boneAuditory canal
FissureSlit through boneAuricular fissure
ForamenHole through boneForamen magnum in the occipital bone
MeatusOpening into canalExternal auditory meatus
SinusAir-filled space in boneNasal sinus
This illustration contains three diagrams. The left diagram is titled examples of processes formed where tendons or ligaments attach. The image shows an anterior view of the femur and an anterior view of the humerus. For the femur, the distal epiphysis contains a smaller lateral bulge and a larger medial bulge. These are examples of condyles. The inner halves of the two condyles as well as the groove between them compose a facet. An oval-shaped ridge on the medial surface of the distal metaphysis is an example of a tubercle. On the proximal epiphysis of the femur, the large knob that attaches to the hip socket is an example of a head. The tip of the head contains a small depression, an example of a fovea called the fovea capitis. On the humerus, the distal epiphysis contains a central depression that is an example of a fossa. Two condyles are located on the right and left sides of the fossa. The diaphysis of the humerus contains a small ridge running up the shaft that is an example of a tuberosity. The proximal epiphysis of the humerus contains a lateral and a medial bulge that are both examples of tubercles. Finally, a narrow groove runs from the center of the proximal metaphysis in between the medial and lateral condyles. This is an example of a sulcus. The middle image is entitled elevations or depressions. It shows an anterior view of the hip bones. The hip bones are shaped like two wings that join at the bottom. The crest along the upper edge of each hip bones, at the tip of each “wing” is an example of an elevation. A depression on the inner surface of both hip bones just under the crest is called out as a fossa. The right image is entitled examples of openings and shows an anterior view of the skull. The bone underlying the chin is an example of a protuberance while two small holes above each eye socket are examples of foramen. Five green sinuses surround the nose cavity are colored green. These are sinuses because they are hollowed out cavities within the skull bones. A small channel leads into the corner of each eye where the tear ducts occur. These two channels are both examples of a canal. Finally, the bones that form the posterior wall of the eye socket have a small crack running diagonally away from the nose. These are examples of fissures.
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You have learned that bone tissue is classified into two types based on structure: compact bone and spongy bone. The parallel arrays of lamellae are organized into different arrangements depending on the bone structure. The lamellae in compact bone form tubular structures, called osteons. The osteons of compact bone are oriented in the direction of the load-bearing axis. The osteons also create a central canal for the passage of blood vessels. Osteocytes in the osteons are embedded in small cavities called lacunae (singular is lacuna), and are oriented around the central canal parallel with the lamellae on the load-bearing axis. The diaphyses of long bones are stronger on their long axis than in any other direction, because of the parallel array of osteons and osteocytes.

The lamellae in spongy bone form a random mesh-like structure of interconnecting plates called trabeculae. Likewise, osteocytes within spongy bone are randomly arranged. The strongest trabeculae in spongy bone are arranged on the bone axis that undergoes the most stress. Flat bones of the skull are primarily made of spongy bone and are good at resisting forces from many directions because of the trabecular arrangement.

In both types of bone tissue, the mineral components, calcium and phosphate, combine with collagen to provide the compressive and tensile strength of bone. Spongy and compact bone tissues are combined to create bones, which store and release calcium and phosphate into the blood through constant resorption and deposition. Many bones then articulate with each other to form the skeletal system.

Ossification Process and Bone Repair Mechanisms

Bones form in two ways. A process known as intramembranous ossification forms bones that develop from layers of connective tissue. Flat bones such as those found in the skull develop through this process. Endochondral ossification (from the word roots endo-, meaning “within,” and chondral, meaning “cartilage”) is bone formation from a hyaline cartilage blueprint or template, which determines the future bone shape. Bones of the limbs and extremities develop through endochondral ossification. For example, an infant’s arm and leg bones contain only small amounts of actual hard bone material; they are primarily made of cartilage. As the child grows, bone replaces the cartilage.

Ossification is the process of forming bone. You learned that there are two types of ossification:

  • intramembranous ossification, which is direct synthesis of bone by specialized stem cells (mesenchymal cells) from fibrous connective tissue; and
  • endochondral ossification, which is synthesis of bone from a (hyaline) cartilage template.

Intramembranous Ossification

Intramembranous ossification is the process that forms and repairs the flat bones of the skull, clavicles and other irregularly shaped bones. In some situations of bone repair and adaptation to excessive force, intramembranous ossification generates new bone.

The process of intramembranous ossification involves multiple steps:

  1. Increased vascularization.
  2. Recruitment of mesenchymal stem cells
  3. Differentiation
  4. Secretion of osteoid
  5. Mineralization
  6. Formation of trabeculae
  7. Formation of outer compact bone

First, the site for future bone formation increases in vascularization—new blood vessels form near the site where the bones will grow. Mesenchymal stem cells, which originate in the embryonic mesoderm, become active and travel through the blood vessels to the future site of bone formation. Chemical messages then cause the mesenchymal stem cells to differentiate: they change into osteoprogenitor cells, which may divide and differentiate into osteoblasts. The osteoblasts deposit osteoid (the unmineralized bone extracellular matrix) and are then trapped in the matrix, where they differentiate into osteocytes. Inorganic salts in the blood travel through the blood vessels to mineralize the bone matrix. As a result, hydroxyapatite crystals form within the osteoid. On the interior of the tissue, small clusters of bone begin to connect with other clusters to form trabeculae. Osteoblasts near the surface of the bone deposit matrix in organized lamellae and form a thin outer layer of compact bone. The periosteum (“peri-” means “surrounding” and “osteum” means “bone”) is living membrane composed of fibrous connective tissue that forms on the outside of the compact bone. Its inside layer has osteoblasts for bone growth and repair.

Endochondral Ossification

Most bones of the skeleton below the skull develop through endochondral ossification.

This process involves the following steps:

  1. Formation of a cartilage template
  2. Growth of the template
  3. Differentiation
  4. Vascularization
  5. Calcification
  6. Bone formation

The first step is formation of a hyaline cartilage template, which is the shape of the desired new bone. The cartilage template grows in size and thickens through the production of new chondroblasts at the perichondrium. The perichondrium is the cartilage equivalent of the periosteum. Chondroblasts differentiate into chondrocytes, which produce chemical messages that stimulate the increase of vascular supply at the perichondrium. This increase in vascular supply brings in inorganic salts, which mineralize the central cartilage matrix.

Cartilage is laid down as a template that provides some mechanical stability. This is like when designers and architects build a template out of balsa wood, clay or foam because it is easy to quickly remodel and manipulate those substances. Then, once the template is worked out, they will remodel it using a stronger material. In bone, the ‘model’ cartilage is remodeled over time and osteoblasts produce a full bone matrix with new collagen and hydroxyapatite. In this way, biology works more efficiently than any engineered tissue graft.

Bone Mechanics, Formation, and Aging

After bone formation, bone resorption and bone deposition occur continually in a process called bone remodeling to allow for skeletal response to mechanical use, nutritional status and as part of the bone repair and healing process. In the absence of malnutrition or disease, this process maintains homeostasis of both total bone mass and inorganic substances such as calcium and phosphate.

As bones age, they tend to decrease in density and, as a consequence, decrease in strength. In some people, especially women, the bones become very brittle and easily broken. The result is a disorder called osteoporosis. Within bones affected by osteoporosis, bone mass and mineral content decrease. As a result, the bones develop canals filled with fibrous and fatty tissues. This leads to an increased risk of bone fracture because the bone organization that is important to weight bearing is lost.



The microscale structure of a bone gives it significant strength and rigidity, but extreme forces can cause bones to break, or fracture. The table below describes the most common types of fractures.

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Fractures weaken bone, making it less able to perform its functions of support and protection, although once healed, the site of the fracture is stronger than the remaining bone. A fracture may cause a change in the shape of the bone. If that happens, then the way the bone responds to a contracted muscle may change. As a result, fractures can prevent bones from moving correctly when muscles pull on them.A bone fracture affects the bone on several levels of organization. A fracture involves a physical break in the mineral structure of the bone. Fractures typically cause blood vessels in the bone to rupture, reducing the blood flow to the bone tissue. As a result, some of the cells in the surrounding bone die. These dead cells and the related cellular debris are removed by immune cells and osteoclasts. Over time, various cell types—fibroblasts, chondroblasts, and osteoblasts—work together to repair the mineralized bone tissue.

There are pain receptors and nerves in the bone. The pain experienced when a fractured bone moves is one way the body reacts to help itself heal. Bones heal more quickly and thoroughly if they are kept immobilized (which is why the typical treatment for a broken bone is to put it in a cast or other restraint). Because we instinctively avoid actions that cause pain, the pain that occurs when a broken bone is moved causes us to minimize the movement of that bone. This, in turn, helps keep the bone stable while it heals.

Severe fractures, such as compound fractures or comminuted fractures, can cause long-term or permanent disruptions to the body’s homeostasis. Because a compound fracture breaks through the skin, bacteria and other pathogens can enter the body after a compound fracture. Those pathogens can enter the bone, blood, muscles, or other tissues or organs, causing severe infection. Severe fractures are also less likely to heal correctly without medical (typically surgical) intervention. Improperly healed fractures can cause changes in the bone’s reaction to force, leading to changes in body motion (such as a limp).

Macroscopic anatomy of a bone
  • Name the precursor to this cell.
  • Answer: This is an osteocyte, which is an osteoblast that has become encased in bone. The embryonic precursor to both of these is the osteoprogenitor cell, a mesenchymal stem cell.

  • Identify the labeled cells.
  • Answer: A = osteoclast; note multiple nuclei. B = osteoblast

  • What will these cells secrete?
  • Answer: Lysosomal hydrolases, collagenase, acid pH

  • What is the pale, blue-staining region?
  • Answer: Epiphyseal Plate

  • What general process causes the circular formations?
  • Answer: Bone remodeling

  • What type of bone formation is taking place?
  • Answer: Endochondral Ossification

  • What is the function of this cell and what is its embryological precursor?
  • Answer: This is an osteoclast, which resorbs bone. It's embryological precursor is a monocyte. In contrast, the precursors of osteoblasts are mesencyhmal stem cells.

  • This slide shows a resorption canal, where new bone is being laid down. Identify A, B, C, D and E
  • Answer: A = osteoblasts, B = osteocytes, C = osteoid, D = cement line E = bone

  • Parathyroid hormone increases the activity of osteoclasts and causes bone to be broken down. However, with an infusion of PTH, there is an initial increase in the creation of new bone matrix. Explain this observation in terms of what you know about osteoclast activation.
  • Answer: Osteoclast activation requires a previous osteoblast activation. For this reason, the brief surge in osteoblast activity associated with PTH causes a transient increase in bone production before a large increase in bone resorption takes place.


    Bone structure macroscopic

    Gross Anatomy

    All the bones in the body can be described as long bones or flat bones.

    Learning Objectives

    Differentiate long bones from flat bones

    Key Takeaways

    Key Points

    • Long bones are those that are longer than they are wide.
    • The end of the long bone is the epiphysis and the shaft is the diaphysis. When a human finishes growing these parts fuse together.
    • The outside of the flat bone consists of a layer of connective tissue called the periosteum.
    • The interior part of the long bone is the medullary cavity with the inner core of the bone cavity being composed of marrow.
    • Flat bones have broad surfaces for protection or muscular attachment.
    • Flat bones are composed of two thin layers of compact bone that surround a layer of cancellous (spongy) bone. In an adult, most red blood cells are formed in the marrow in flat bones.

    Key Terms

    • endosteum: A thin vascular membrane of connective tissue that lines the surface of the bone tissue that forms the medullary cavity of long bones.
    • medullary cavity: The medullary cavity, also known as the marrow cavity, is the central cavity of bone shafts where red bone marrow and/or yellow bone marrow (adipose tissue) is stored.
    • diaphysis: The central shaft of any long bone.
    • epiphyseal plate: A hyaline cartilage plate in the metaphysis, located at each end of a long bone where growth occurs in children and adolescents.

    Bone Tissue

    Bones support and protect the body and its organs. They also produce various blood cells, store minerals, and provide support for mobility in conjunction with muscle. Bone is made of bone tissue, a type of dense connective tissue.

    Bone (osseous) tissue is the structural and supportive connective tissue of the body that forms the rigid part of the bones that make up the skeleton. Overall, the bones of the body are an organ made up of bone tissue, bone marrow, blood vessels, epithelium, and nerves.

    There are two types of bone tissue: cortical and cancellous bone. Cortical bone is compact bone, while cancellous bone is trabecular and spongy bone.

    Cortical bone forms the extremely hard exterior while cancellous bone fills the interior. The tissues are biologically identical but differ in the arrangement of their microstructure.

    Bone Cells

    The following are the different types of bone cells:

    • Osteoblasts-involved in the creation and mineralisation of bone
    • Osteocytes and osteoclasts: These are involved in the reabsorption of bone tissue. The mineralized matrix of bone tissue has an organic component—mainly made of collagen—and an inorganic component of bone mineral made up of various salts.

    Bone Types

    There are different types of bone. These are:

    • Long bones
    • Short bones
    • Flat bones
    • Sesamoid bones
    • Irregular bones
    This image show the different bone classifications, based on shape, that are found in a human skeleton. These are flat bone, sutural bone, short bone, irregular bone, sesamoid bone, and long bone.

    Bone types: This image show the different bone classifications, based on shape, that are found in a human skeleton. These are flat bone, sutural bone, short bone, irregular, sesamoid bone, and long bone.

    Long Bones

    This is a drawing of a long bone (femur). It shows how a long bone is longer than it is wide. Growth occurs by a lengthening of the diaphysis, located in the center of the long bone.

    Long bone: A long bone is longer than it is wide. Growth occurs by a lengthening of the diaphysis. located in the center of the long bone.

    Long bones grow primarily by elongation of the diaphysis (the central shaft), with an epiphysis at each end of the growing bone. The ends of epiphyses are covered with hyaline cartilage (articular cartilage). At the cessation of growth, the epiphyses fuse to the diaphysis, thus obliterating the intermediate area known as the epiphyseal plate or growth plate. The long bones in the body are as follows:

    • Legs: The femur, tibia, and fibula.
    • Arms: The humerus, radius, and ulna.
    • The clavicles or collar bones.
    • Metacarpals, metarsals, phalanges.

    The outside of the bone consists of a layer of connective tissue called the periosteum. The outer shell of the long bone is compact bone, below which lies a deeper layer of cancellous bone (spongy bone), as shown in the following figure. The interior part of the long bone is called the medullary cavity; the inner core of the bone cavity is composed of marrow.

    Short Bones

    Short bones are about as wide as they are long. These provide support with less movement. Examples of short bones include the carpal and tarsal bones of the wrist and feet. They consist of a thin layer of cortical bone with cancellous interiorly.

    This is a color drawing of compact bone and spongy bone. The hard outer layer of bones is shown to be made of compact bone tissue, so-called due to its minimal gaps and spaces. Its porosity is 5–30%. Inside the interior of the bone is the trabecular bone tissue, an open cell, porous network that is also called cancellous or spongy bone.

    Compact bone and spongy bone: The hard outer layer of bones is composed of compact bone tissue, so-called due to its minimal gaps and spaces. Its porosity is 5–30%. Inside the interior of the bone is the trabecular bone tissue, an open cell, porous network that is also called cancellous or spongy bone. 

    Flat Bones

    Flat bones are broad bones that provide protection or muscle attachment. They are composed of two thin layers of compact bone surrounding a layer of cancellous (spongy) bone.

    These bones are expanded into broad, flat plates, as in the cranium (skull), ilium (pelvis), sternum, rib cage, sacrum, and scapula. The flat bones are named:

    • Occipital
    • Parietal
    • Frontal
    • Nasal
    • Lacrimal
    • Vomer
    • Scapula
    • Os coxæ (hip bone)
    • Sternum
    • Ribs

    Sesamoid Bone

    Sesamoid bones are smaller bones that are fixed in tendons to protect them. An example is the patella (knee cap) located in the patellar tendon. Other examples include the small bones of the metatarsals and the pisiform bones of the carpus.

    Irregular Bone

    The irregular bones are named for their nonuniform shape. Examples include the bones of the vertebrae. These typically have a thin cortical layer with more cancellous bone in their tissue.

    Supply of Blood and Nerves to Bone

    The blood and nerve supply to bones are carried in Haversian canals that run along the long axis of bones.

    Learning Objectives

    Describe the blood and nerve supply of bones

    Key Takeaways

    Key Points

    • Haversian canals typically run parallel to the surface and along the long axis of the bone and generally contain one or two capillaries and nerve fibers.
    • Volkmann’s canals are channels that assist with blood and nerve supply from the periosteum to the Haversian canal.
    • The vascular supply of long bones depends on several points of inflow.
    • Except for a few with double or no foramina (places in bone where capillaries enervate), 90% of long bones have a single nutrient foramen in the middle third of the shaft.
    • Young periosteum is more vascular and its vessels communicate more freely with those of the shaft compared to adult periosteum.

    Key Terms

    • perichondrium: A layer of dense irregular connective tissue that surrounds the cartilage of developing bone.
    • Volkmann’s canal: Also known as perforating holes, these are microscopic structures found in the compact bone that carry small arteries throughout the bone.
    • anastomose: Joined or run together.
    • Haversian canal: A hollow channel in the center of an osteon, running parallel to the length of a bone.

    Blood is supplied to mature compact bone through the Haversian canal. Haversian canals are formed when individual lamellae form concentric rings around larger longitudinal canals (approx. 50 µm in diameter) within the bone tissue.

    Haversian canals typically run parallel to the surface and along the long axis of the bone. The canals and the surrounding lamellae (8–15) are called a Haversian system or an osteon. A Haversian canal generally contains one or two capillaries and nerve fibers.

    The Haversian canals also surround nerve cells throughout the bone and communicate with osteocytes in lacunae (spaces within the dense bone matrix that contain the living bone cells) through canaliculi. This unique arrangement is conducive to the storage of mineral salt deposits that give bone tissue its strength.

    This is an exploded view of a Haversian canal. The Haversian canals surround blood vessels and nerve cells throughout the bone.

    Haversian canal: The Haversian canals surround blood vessels and nerve cells throughout the bone.

    The vascular supply of long bones depends on several points of inflow, which feed complex sinusoidal networks within the bone. These in turn drain to various channels through all surfaces of the bone except that covered by articular cartilage.

    This is a drawing of a long bone that depicts its parts. It shows the location of the epiphyseal plates (or lines) and the articular surfaces of long bones, within the epiphysis on each end of the bone.

    Epiphyseal plate: Image shows the location of the epiphyseal plates (or lines) and the articular surfaces of long bones.

    Volkmann’s canals are channels that assist with blood and nerve supply from the periosteum to the Haversian canal. One or two main diaphyseal nutrient arteries enter the shaft obliquely through one or two nutrient foramina leading to nutrient canals. Their sites of entry and angulation are almost constant and characteristically directed away from the growing epiphysis.

    Except for a few with double or no foramina, 90% of long bones have a single nutrient foramen in the middle third of the shaft. The nutrient arteries divide into ascending and descending branches in the medullary cavity. These approach the epiphysis dividing into smaller rami. Near the epiphysis, they anastomose with the metaphyseal and epiphyseal arteries.

    The blood supply of the immature bones is similar, but the epiphysis is a discrete vascular zone separated from the metaphysis by the growth plate. Epiphyseal and metaphyseal arteries enter on both sides of the growth cartilage, with anastamoses between them being few or absent.

    Growth cartilage receives its blood supply from both sources and also from an anastamotic collar in the adjoining perichondrium. Young periosteum is more vascular, has more metaphyseal branches, and its vessels communicate more freely with those of the shaft than adult periosteum.

    Microscopic Anatomy of Bone

    The basic microscopic unit of bone is an osteon, which can be arranged into woven bone or lamellar bone.

    Learning Objectives

    Classify woven bone and lamellar bone

    Key Takeaways

    Key Points

    • Woven bone is found on the growing ends of an immature skeleton or, in adults, at the site of a healing fracture.
    • Woven bone is characterized by the irregular organization of collagen fibers and is mechanically weak, but forms quickly.
    • Lamellar bone is much stronger than woven bone, and is highly organized in concentric sheets with a much lower proportion of osteocytes to mineralized tissue.
    • When the same lamellar bone is loosely arranged, it is referred to as trabecular bone. Trabecular bone gets its name because of the spongy pattern it displays on an x-ray.
    • After a fracture, woven bone forms initially and is gradually replaced by lamellar bone during a process known as bony substitution.

    Key Terms

    • osteoblast: A mononucleate cell from which bone develops.
    • osteocytes:  A star-shaped type of bone cell that is found in the cells of mature bone.
    • lamellar bone: A bone with a regular, parallel alignment of collagen into sheets (lamellae) that is mechanically strong.
    • woven bone: Characterized by an irregular organization of collagen fibers, this bone is mechanically weak.

    Bones are composed of bone matrix, which has both organic and inorganic components. Bone matrix is laid down by osteoblasts as collagen, also known as osteoid. Osteoid is hardened with inorganic salts, such as calcium and phosphate, and by the chemicals released from the osteoblasts through a process known as mineralization.

    The basic microscopic unit of bone is an osteon (or Haversian system). Osteons are roughly cylindrical structures that can measure several millimeters long and around 0.2 mm in diameter.

    Each osteon consists of a lamellae of compact bone tissue that surround a central canal (Haversian canal). The Haversian canal contains the bone’s blood supplies. The boundary of an osteon is called the cement line. Osteons can be arranged into woven bone or lamellar bone.

    This is a photo taken through a microscope that shows the anatomy of compact bone with a detailed view of an osteon. The Haversian system is called out in the osteon: The Haversian canal, lacuna and osteocype, and the canaliculi are identified.

    Osteon: A photo taken through a microscope that shows the anatomy of compact bone with a detailed view of an osteon.

    Woven Bone

    This is a photo of woven bone seen through a microscope. Woven bone is characterized by the irregular organization of collagen fibers seen in this picture, and it is mechanically weak.

    Woven bone: Woven bone is characterized by the irregular organization of collagen fibers and is mechanically weak.

    Woven bone is found on the growing ends of an immature skeleton or, in adults, at the site of a healing fracture. Woven bone is characterized by the irregular organization of collagen fibers and is mechanically weak, but forms quickly.

    The criss-cross appearance of the fibrous matrix is why it is referred to as woven. It has a high proportion of osteocytes to hard inorganic salts that leads to its mechanical weakness.

    Woven bone is replaced by lamellar bone during development. In contrast to woven bone, lamellar bone is highly organized in concentric sheets with a much lower proportion of osteocytes to surrounding tissue. The regular parallel alignment of collagen into sheets, or, lamellae, causes lamellar bone to be mechanically strong.

    Lamellar Bone

    This is a closeup, cross-section photo of the head of a femur. The head of the femur shows lamellar bone on its borders and trabecular bone in its center.

    Femur head showing trabecular bone: A cross-section of the head of the femur showing lamellar bone on the borders and trabecular bone in the center.

    Lamellar bone makes up the compact or cortical bone in the skeleton, such as the long bones of the legs and arms. In a cross-section, the fibers of lamellar bone can be seen to run in opposite directions in alternating layers, much like in plywood, assisting in the bone’s ability to resist torsion forces.

    When the same lamellar bone is loosely arranged, it is referred to as trabecular bone. Trabecular bone gets its name because of the spongy pattern it displays in an x-ray. The spaces within trabecular bone are filled with active bone marrow.

    After a fracture, woven bone forms initially, but it is gradually replaced by lamellar bone during a process known as bony substitution.

    Chemical Composition of Bone

    Acid-base imbalances, including metabolic acidosis and alkalosis, can produce severe, even life-threatening medical conditions.

    Learning Objectives

    Differentiate among the acid-base disorders

    Key Takeaways

    Key Points

    • Metabolic acidosis can produce, among other symptoms, chest pains, altered mental states, nausea, abdominal pain, and muscle weakness.
    • Rapid, deep breathing during metabolic acidosis is an attempt to lower carbon dioxide levels and return pH to normal.
    • Extreme acidemia can lead to coma, seizures, heart arrhythmias, and low blood pressure.
    • Slowed breathing, which results in retaining more CO2, is the primary method of reducing metabolic alkalosis.
    • Chronic respiratory acidosis is a result of COPD, obesity hypoventilation syndrome, ALS, and thoracic deformities.
    • Respiratory alkalosis can be caused by excessive mechanical ventilation, psychiatric problems, stroke, drug use, traveling to high altitude regions, lung disease, fever, and pregnancy, among other factors.

    Key Terms

    • metabolic alkalosis: A metabolic condition in which the pH of tissue is elevated beyond the normal range ( 7.35 to 7.45 ). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate concentration, or a direct result of increased bicarbonate concentration.
    • respiratory acidosis: A medical condition in which decreased ventilation (hypoventilation) causes increased blood carbon dioxide concentration and decreased pH (a condition generally called acidosis).
    • metabolic acidosis: A condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body.


    Traveling to a high altitude can cause an acid-base imbalance due to reduced levels of oxygen in the atmosphere, and, therefore, in the blood. To compensate for this, the traveler begins to hyperventilate, trying to expel excess carbon dioxide and bring pH back to normal. However, if the traveler stays at high altitude, it may take several days for their pH to fully return to normal.

    Acid-Base Disorders

    Acid-base imbalance is an abnormality of the human body’s normal balance of acids and bases that causes the plasma pH to deviate out of normal range (7.35 to 7.45). In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.18 to 7.38). Acid-base imbalances can exist in varying levels of severity, some life-threatening.

    An excess of acid is called acidosis and an excess in bases is called alkalosis. The process that causes the imbalance is classified based on the etiology of the disturbance (respiratory or metabolic) and the direction of change in pH (acidosis or alkalosis).

    Mixed disorders may feature an acidosis and alkalosis excess at the same time that partially counteract each other, or there can be two different conditions affecting the pH in the same direction. The phrase mixed acidosis, for example, refers to metabolic acidosis in conjunction with respiratory acidosis.

    Metabolic Acidosis

    In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, that is, blood pH is less than 7.35 due to increased production of hydrogen by the body, or because of the body’s inability to form bicarbonate (HCO3-) in the kidneys.

    Acidosis refers to a low pH in tissue. Acidemia refers to a low pH in the blood. Symptoms may include chest pain, palpitations, headache, altered mental status such as severe anxiety due to hypoxia, decreased visual acuity, nausea, vomiting, abdominal pain, altered appetite (either loss of or increased) and weight loss (longer term), muscle weakness, and bone pains.

    Rapid deep breaths increase the amount of carbon dioxide exhaled, thus lowering the serum carbon dioxide levels, resulting in some degree of compensation. Overcompensation via respiratory alkalosis to form an alkalemia does not occur.

    Neurological complications include lethargy, stupor, coma, seizures. Cardiac complications include arrhythmias (ventricular tachycardia) and decreased response to epinephrine; both lead to hypotension (low blood pressure).

    Metabolic Alkalosis

    Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range (7.35 to 7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate concentration, or as a direct result of increased bicarbonate concentrations. Alkalosis refers to a high pH in tissue.

    Alkalemia refers to a high pH in the blood. The causes of metabolic alkalosis can be divided into two categories, depending upon urine chloride levels. Chloride-responsive causes result from the loss of hydrogen ions via vomiting or the kidneys. Vomiting results in the loss of hydrochloric acid (hydrogen and chloride ions) with the stomach contents.

    The kidneys compensate for these losses by retaining sodium in the collecting ducts at the expense of hydrogen ions (sparing sodium/potassium pumps to prevent further loss of potassium), and leads to metabolic alkalosis. The excess sodium increases extracellular volume and the loss of hydrogen ions creates a metabolic alkalosis.

    Later, the kidneys respond through the aldosterone escape to excrete sodium and chloride in urine. Compensation for metabolic alkalosis occurs mainly in the lungs, which retain carbon dioxide (CO2) through slower breathing, or hypoventilation (respiratory compensation).

    CO2 is then consumed towards the formation of the carbonic acid intermediate, thus decreasing pH. Renal compensation for metabolic alkalosis, less effective than respiratory compensation, consists of increased excretion of HCO3– (bicarbonate), as the filtered load of HCO3– exceeds the ability of the renal tubule to reabsorb it.

    Respiratory Acidosis

    Respiratory acidosis is a medical condition in which decreased ventilation (hypoventilation) causes an increase in blood carbon dioxide concentration and decreased pH (a condition generally called acidosis). Carbon dioxide is produced constantly as the body’s cells respire, and this CO2 will accumulate rapidly if the lungs do not adequately expel it through alveolar ventilation.

    Acute respiratory acidosis occurs when an abrupt failure of ventilation occurs. This failure in ventilation may be caused by depression of the central respiratory center by cerebral disease or drugs, an inability to ventilate adequately due to neuromuscular disease (e.g., myasthenia gravis, amyotrophic lateral sclerosis, Guillain-Barré syndrome, muscular dystrophy), or airway obstructions related to asthma or chronic obstructive pulmonary disease (COPD) exacerbation.

    Respiratory Alkalosis

    Respiratory alkalosis is a medical condition in which increased respiration (hyperventilation) elevates the blood pH (a condition generally called alkalosis). There are two types of respiratory alkalosis: chronic and acute.

    Acute respiratory alkalosis occurs rapidly. During acute respiratory alkalosis, the person may lose consciousness whereupon the rate of ventilation will resume to normal.

    Chronic respiratory alkalosis is a more long-standing condition. Respiratory alkalosis may be produced accidentally (iatrogenically) during excessive mechanical ventilation. Other causes include: psychiatric causes, drug use, fever, and pregnancy.

    Microscopic structure of bone - the Haversian system - NCLEX-RN - Khan Academy

    Specialized connective tissue: bone, the structural framework of the upper extremity

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