Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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Dual-Energy X-Ray Absorptiometry

0049 DEXA is a recent addition to the body composition

analysis field. It was originally developed to measure

regional and total-body bone mineral content, but it

is also capable of measuring fat mass. It is more

sensitive than dual-photon absorptiometry, which it

has now replaced, and exposes the subject to substan-

tially lower radiation doses than total-body calcium

measured by neutron activation analysis.

0050 The DEXA technique exposes the subject to low

energy irradiation at two different energies. As there

is differential absorption by tissues of different

densities (bone, lean and fat tissues), values for bone

mineral in the hip, spine, whole body, or specialized

regions, as well as values for fat or soft tissues, can be

derived.

0051 It is a sensitive technique for determining bone

mineral content and densities, and has become the

gold standard for clinical and research work in osteo-

porosis.

0052 Because the fat-free nonbone component of the

limbs effectively measures limb skeletal muscle

mass, of which the proportion to whole-body skeletal

muscle is fairly constant, DEXA can be used to meas-

ure skeletal muscle mass.

Other Techniques

0053 Other techniques for measuring body composition

include CT scanning and MRI. These techniques

have been used for accurate measurement of various

body compartments. These compartments include

visceral adipose tissue mass, increased amounts of

which are related to risk for diabetes and vascular

disease, and skeletal muscle volume. Whilst their clin-

ical and research use is limited by expense, availabil-

ity, and, in the case of CT scanning, patient exposure

to ionizing radiation, much helpful information has

been obtained from the research groups who have

utilized such technology.

Error of the Methods

0054 Each of the methods for measuring body composition

has intrinsic and biological errors. In general, these

are very comparable to the errors of biochemical

methods commonly performed in hospital labora-

tories (Table 3).

Effect of Disease Processes on Human

Body Composition

Obesity

0055 The fat compartment – expressed as mass or percent-

age fat – has importance as an expression of adiposity.

The association between increased adiposity and

morbidity is well documented. The incidence of

diabetes, hypertension, ischemic heart disease, and

gallbladder disease is increased at higher levels of

adiposity.

0056Fat distribution is being increasingly recognized as

a clinically relevant risk factor. Abdominal obesity,

expressed as the abdominal circumference-to-gluteal-

circumference ratio, has been shown, independent of

other factors, to represent an increased risk for mor-

bidity and mortality. First described in the 1950s, this

association has been verified and strengthened by

intense research interest in the last decade. More

recently, the abdominal circumference alone has also

been shown to predict morbidity and mortality. The

correlation is not just an epidemiological one: many

metabolic abnormalities, such as insulin resistance,

are associated with this condition.

0057With increasing adiposity, it is usual to find an

increase in lean mass. This occurs because of the

increased skeletal muscle mass required to carry the

increased fat mass.

0058In obese people who have undergone repeated

near-starvation dieting, there may be marked wasting

of skeletal muscle, even in the presence of adiposity.

Similarly, muscle wasting, or even marasmus, can

occur in the obese person who has concomitant severe

illness. For example, a chronic alcoholic with a poor

quality of food intake and liver impairment may be

obese (excess fat stores) and also have skeletal muscle

wasting.

Undernutrition

0059In global terms, undernutrition remains one of the

greatest determinants of health status. The most

common expressions of undernutrition are commonly

known as kwashiorkor and marasmus. Intermediate

forms are commonly seen. In marasmus, there is a

wasting of total-body protein without expansion of

the TBW compartment. In kwashiorkor, there is an

expansion of the extracellular component of TBW,

giving rise to peripheral edema and ascites. Exactly

why undernutrition results in these two different

forms remains unclear.

0060Both forms are associated with a reduction in the

capacity of the cell-mediated immune system of

the body, giving rise to an increased risk of infec-

tion. Where food intake is reduced, it is likely that

other nutrient deficiencies, such as iron, folate, or

vitamin A deficiency, will be present and may mask

the extent of the underlying body composition

changes.

0061In developing countries, these forms of undernutri-

tion usually arise from the combination of inadequate

food resources and chronic infection. In malnutrition

BODY COMPOSITION 555

caused by inadequate food intake, many studies

have shown an increase in the ratio of extracellular

fluid volume to TBW. Electrolyte abnormalities are

common. Reduced levels of sodium, potassium, and

magnesium may be found. Protein stores, as meas-

ured by IVNAA and expressed as nitrogen index, are

reduced.

0062 In developed countries, these conditions are fre-

quently seen in conjunction with malignancy, psychi-

atric conditions, organ failure, and conditions in

which self-feeding is difficult, e.g., stroke or arth-

ritis. (See Malnutrition: Malnutrition in Developed

Countries.)

0063 The wasting seen in many malignancies, even when

nutritional intake and absorption is apparently ad-

equate, may be caused by cytokines such as cachectin

and tumor necrosis factor.

0064 Visceral mass may be better preserved in cancer

patients, suggesting that loss of muscle accounts for

the major proportion of weight loss. This may be

the result of a difference in metabolic rate between

malignancy and anorexia; the rate is often increased

in patients with malignancy, but reduced in anorexia

nervosa. (See Anorexia Nervosa.)

0065 In anorexia nervosa, many of the body compos-

ition changes seen are similar to those found in

starved subjects. Total-body nitrogen, total-body

potassium, and blood volume are all reduced. Unlike

primary starvation, extracellular water may be re-

duced by relatively greater amounts than the reduc-

tion in TBW owing to induced vomiting or purging.

Interestingly, many patients with anorexia nervosa

maintain normal levels of hemoglobin and serum

albumin and rarely exhibit vitamin deficiencies or

develop edema.

Conclusion

0066 An understanding of body composition and its meas-

urement provides the clinician with further scientific

data on which to base a nutritional assessment.

Advances in this area are now available to provide

accurate measurements which previously could only

be estimated. Some of these techniques are easily

applicable to office general practice or field studies,

whilst others require more sophisticated equipment

which is only available in specialized centres. Body

composition changes in health and disease help to

explain the pathogenesis of illnesses which involve

alteration in food intake or absorption and

metabolism.

See also: Anorexia Nervosa; Malnutrition: Malnutrition

in Developed Countries; Osteoporosis

Further Reading

Alleyne GEO (1975) Mineral metabolism in protein-calorie

malnutrition. In: Olsen RE (ed.) Protein-Calorie Mal-

nutrition, pp. 201–208. New York: Academic Press.

Brozek J, Grande F, Anderson IT and Keys A (1963) Densi-

tometric analysis of body composition: revision of some

quantitative assumptions. Annals of the New York

Academy of Sciences 110: 113–140.

Durnin JVGA and Womersley J (1974) Body fat assessed

from body density and its estimation from skin fold

thickness: measurements on 481 men and women aged

from 16 to 72 years. British Journal of Nutrition 32:

77–97.

Forbes GB (1987) Human Body Composition, pp. 2–171.

New York: Springer-Verlag.

Forbes GB (1990) Body composition. In: Brown M (ed.)

Present Knowledge in Nutrition, 6th edn. Washington,

DC: International Life Sciences Institute.

Forbes GB, Kriepe RE, Lipinski BA and Hodgman CH

(1984) Body composition changes during recovery

from anorexia nervosa: comparison of two dietary

regimes. American Journal of Clinical Nutrition 40:

1137–1145.

Fowler PA, Fuller MF, Glasby CA et al. (1991) Total and

subcutaneous adipose tissue in women: the measurement

of distribution and accurate prediction of quality by

using magnetic resonance imaging. American Journal

of Clinical Nutrition 54: 18–25.

Hastings AB and Eichelberger L (1937) The exchange of

salt and water between muscle and blood. Journal of

Biological Chemistry 117: 73–93.

International Commission on Radiological Protec-

tion(1975) Report of the Task Group on Reference

Man, no. 23. Oxford: Pergamon Press.

Jelliffe EPP and Jelliffe DB (1969) The arm circumference as

a public health index of protein-calorie malnutrition

of early childhood. Journal of Tropical Paediatrics 15:

179–192.

Kvist H, Choudury B, Grangard U, Tyler U and Sjostrom L

(1988) Total and visceral adipose tissue volumes derived

from measurements with computed tomography in adult

men and women: predictive equations. American Jour-

nal of Clinical Nutrition 48: 1351–1361.

Lohman TG (1981) Skin-folds and body density and their

relation to body fatness: a review. Human Review 53:

181–225.

Lukaski HC (1987) Methods for the assessment of human

body assess human body composition. Journal of

Applied Physiology 60: 1327–1332.

Lukaski HL, Johnson PE, Bolonchuk WW et al. (1985)

Assessment of fat-free mass using bioelectrical imped-

ance measurements of the human body. American Jour-

nal of Clinical Nutrition 41(4): 810–817.

Mazess RB, Collick B, Trempe J, Barden HS and Hanson JA

(1989) Performance evaluation of a dual-energy x-ray

bone densitometer. Calcified Tissue International 44:

228–232.

Mazess RB, Barden HS, Bisek JP and Hanson J (1990) Dual

energy X-ray absorptiometry for total body and regional

556 BODY COMPOSITION

bone mineral and soft tissue composition. American

Journal of Clinical Nutrition 51: 1106–1112.

Mazess RB, Hanson JA, Trempe J and Bonnick SL (1991)

Ultrasound Measurement of the Os Calcis. Proceedings

of the 8th International Workshop on Bone Densitome-

try, 28 April, Bad Reichenhall, FRG.

Ross R, Goodpaster B, Kelley D and Fernando B (2000)

Magnetic resonance imaging in human body compos-

ition research: from quantitative to qualitative tissue

measurement. Annals of the New York Academy of

Science 904: 12–17.

Stroud DB, Borovnicar DJ, Lambert JR et al. (1990) Clin-

ical studies of total body nitrogen in an Australian hos-

pital. In: Yasurnura S (ed) In vivo Body Composition

Studies, Basic Life Sciences, vol. 55, pp. 177–182.New

York: Plenum Press.

Vague J (1956) The degree of masculine differentiation of

obesities: a fact for determining predisposition to

diabetes, atherosclerosis, gout, uric calculus disease.

American Journal of Clinical Nutrition 4: 20–34.

Wang ZM, Pierson RN and Heymsfield SB (1992) The five

level model: a new approach to body composition

research. American Journal of Clinical Nutrition 56:

19–28.

Widdowson EM and Dickerson JWT (1964) Chemical

composition of the body. In: Comari CL and Bronner F

(eds) Mineral Metabolism, vol. 2, part A, pp. 2–

247.London: Academic Press.

BONE

K D Cashman, University College, Cork, Ireland

F Ginty, MRC Human Nutrition Research, Cambridge,

Introduction

0001 Bone is a specialized connective tissue that makes

up, together with cartilage, the skeletal system. The

skeleton serves three important functions: (1) mech-

anical; support and site of muscle attachment for

locomotion; (2) protective; for vital organs and

bone marrow; and (3) metabolic, as a reserve for

ions, especially calcium and phosphate; for the

maintenance of serum homeostasis, which is critical

to life.

0002 In bone, as in all connective tissues, the fundamen-

tal constituents are the cells and the extracellular

matrix (the osteoid). Osteoid is particularly abundant

in bone and is composed of collagen fibers and non-

collagenous proteins. Bone is distinguished from

other forms of connective tissue by the fact that it

becomes extremely hard, owing to the deposition

within a relatively soft organic matrix of a complex

mineral substance, largely composed of calcium,

phosphate, and carbonate. Bone is built up during

youth to a peak reached probably in the 20s. It then

diminishes again, first slowly, then more rapidly,

especially in women after the menopause, and in

both sexes in the elderly. The regulation of this skel-

etal growth and development is complex and involves

genetic, mechanical, hormonal, and nutritional influ-

ences. At a cellular level, bone metabolism or remod-

eling is coordinated by a multiplicity of interacting

local hormones, cytokines, and growth factors. Such

bone-associated factors may play a role in the patho-

physiology of bone disorders.

Anatomical Features of Bone

0003Anatomically, two types of bone can be distinguished

in the skeleton: flat bones (i.e., the skull bones,

scapula, mandible, and ilium) and long bones (tibia,

femur, humerus, etc.). External examination of a long

bone (Figure 1) shows the two wider extremities (the

epiphyses), a more or less cylindrical tube in the

middle (the diaphysis or midshaft), and a develop-

ment zone between them (the metaphysis). In a grow-

ing bone, the epiphysis and the metaphysis, which

originate from two independent ossification centers,

are separated by a layer of cartilage, the epiphyseal

cartilage or growth plate, which has an important

role in the longitudinal growth of bones. The external

part of bone is formed by a thick and dense layer of

calcified tissue, the cortex or compact bone, which in

the diaphysis encloses the medullary cavity where the

hematopoietic bone marrow is housed. Cortical bone

makes up about 80% of the total skeleton. Toward

the metaphysis and the epiphysis, the cortex becomes

progressively thinner, and the inner space is filled

with a network of thin, calcified trabeculae: this is

cancellous bone, also named spongy or trabecular

bone. The spaces enclosed by these thin trabeculae

also are filled with hematopoietic bone marrow and

are in continuity with the medullary cavity of the

diaphysis. Cancellous bone is also found in the verte-

brae and the majority of flat bones. It makes up about

20% of the total skeleton. The relative proportions of

cortical and cancellous bone differ at different sites in

BONE 557

the skeleton (e.g., cancellous bone comprises > 66%

of the total bone in the lumbar spine, but only 25% of

the total bone in the neck of the femur). The bone

surfaces at the epiphyses that take part in the joint are

covered with a layer of articular cartilage that does

not calcify.

0004 There are two bone surfaces at which the bone is in

contact with the soft tissues (Figure 1): an external

surface (the periosteal surface) and an internal surface

(the endosteal surface). The surfaces are lined with

osteogenic cells organized in layers, the periosteum

and the endosteum. Cortical and trabecular bone are

constituted of the same cells and the same matrix

elements, but there are structural and functional dif-

ferences. The primary structural difference is quanti-

tative: 80–90% of the volume of compact bone is

calcified, whereas only 15–25% of the trabecular

bone is calcified (the remainder is occupied by bone

marrow, blood vessels, and connective tissue). The

result is that 70–85% of the interface with soft tissues

is at the endosteal bone surface, which leads to the

functional difference: the cortical bone fulfills mainly

a mechanical and protective function, while the trab-

ecular bone has a metabolic function. Therefore, at a

macroscopic level, bone can be regarded as an outer

cortical sheath and an inner three-dimensional

trabecular network, which together allow optimal

mechanical and biochemical function with minimal

weight.

Bone Matrix and Mineral

0005Chemically, bone is made up of one-third protein

matrix and two-thirds mineral. Bone matrix is

formed by type I collagen fibers (which make up

90% of the total protein of bone) and numerous

noncollagenous proteins (which make up the

remaining 10% of total protein of bone; Table 1).

Type I collagen is a highly cross-linked fibrillar

protein which, through its tridimensional structure

similar to rope, gives bone its tensile strength. The

functions of the noncollagenous proteins are diverse

and some are still poorly understood (Table 1). The

urinary excretion and the plasma or serum con-

centrations of some of these components of the

matrix are used chemically to assess bone metabolism

(Table 1). Spindle- or plate-shaped crystals of

hydroxyapatite Ca

(PO

)

(OH)

are found on and

within the collagen fibers. They tend to be oriented in

the same direction as the collagen fibers.

0006The preferential orientation of the collagen fibers

alternates in adult bone from layer to layer, giving to

this bone a typical lamellar structure. The lamellae

can be parallel to each other if deposited along a flat

surface (trabecular bone and periosteum), or concen-

tric if deposited on a surface surrounding a channel

centered on a blood vessel. In cortical bone, the tissue

is mainly organized as Haversian systems which rep-

resent its basic structural building blocks (Figure 1).

Epiphyseal cartilage

Haversian system

Canaliculi

Lamellae

Haversian canal

Endosteum

Osteoblast

Lacuna

Periosteum

Cancellous bone

Compact bone

Periosteum

Endosteum

Epiphysis

Metaphysis

Diaphysis

fig0001 Figure 1 Schematic view of a longitudinal section through a long bone (insert; transverse section through the diaphysis).

558 BONE

Each Haversian system is made up of a central canal,

the Haversian canal, which contains an artery, a vein,

a lymphatic vessel, a nerve, and some bone cells. This

is surrounded by successive rings of lamellae. Lying

between the lamellae are a number of small cavities,

the lacunae, which contain bone cells, or osteocytes.

Fine protoplasmic processes from the osteocytes

branch profusely throughout the matrix in very

small canal-like structures, the canaliculi (Figure 1).

These serve to interconnect the lacunae. Lamellar

bone is the form present in adult cortical and cancel-

lous bone. However, when bone is being formed very

rapidly (during embryonic development and fracture

healing), there is no preferential organization of the

collagen fibers. They are not so tightly packed and

found in somewhat randomly oriented bundles. This

type of bone is called woven bone. This immature

bone is usually replaced by lamellar bone, so that it

is practically absent from the adult skeleton, except

for some that may persist near tendon insertions and

ligament attachments.

Bone Cells

0007Bone is a dynamic connective tissue, comprising an

exquisite assembly of functionally distinct cell popu-

lations that are required to support its structural,

biochemical, and mechanical integrity and its central

role in mineral homeostasis. Bone tissue (both cor-

tical and cancellous bone) is constantly turned over

by two cell-mediated processes, bone modeling and

bone remodeling. In the former, new bone is formed

at a location different from the one where it was

destroyed (resorbed). This allows bone to elongate

and widen, altering the shape of the skeleton. This

change takes place principally in the child and ado-

lescent, allowing the development of a normal archi-

tecture during growth. It is also the process by which

vertebrae increase in size during life. During adult-

hood, bone remodeling is the primary process of bone

turnover, however, modeling does continue to take

place at certain skeletal sites such as the periosteum.

The physiological repair of fractured bone is also

tbl0001 Table 1 Principal noncollagenous proteins in the bone matrix

Protein type/name Potential function(s)

Serum proteins

Albumin Transports proteins; inhibits hydroxyapatite crystal growth

a-2HS glycoprotein Promotes endocytosis; chemoattractant for monocytic cells; mineralization inhibitor

Glycoproteins

Alkaline phosphatase

A phosphotransferase; potential Ca

2þ

carrier; hydrolyzes inhibitors of mineral deposition

Osteonectin May mediate deposition of hydroxyapatite; binds to growth factors; may influence cell-cycle

antiadhesive protein

Tetranectin Binds to plasminogen; may regulate matrix mineralization

RGD-containing glycoproteins

Thrombospondins (I,II,III,IV) Cell attachment

Fibronectin Binds to cells

Vitronectin Cell-attachment protein

Osteopontin Binds to cells; inhibits mineralization; may regulate proliferation; inhibits nitric oxide

synthase; may regulate tissue repair

Bone sialoprotein

Binds to cells; binds Ca

2þ

with high affinity; may initiate mineralization

BAG-75 Binds to Ca

2þ

; may act as a cell-attachment protein; may regulate bone resorption

g-Carboxy glutamic acid-

containing proteins

Matrix Gla protein May function in cartilage metabolism, may inhibit mineralization

Osteocalcin

May regulate activity of osteoclasts and their precursors; may mark turning point between

bone formation and resorption; regulates mineral maturation

Protein S Protein S-deficiency may result in osteopenia

Glycosaminoglycan-containing

Veriscan May ‘capture’ space that is destined to become bone,

Decorin Binds to collagen and may regulate fibril diameter; binds to TGF-b; inhibits cell

attachment to fibronectin

Biglycan May bind to TGF-b

Fibromodulin Binds to collagen; may regulate fibril formation; binds to TGF-b

Osteoadherin May mediate cell attachment

Hyaluroan May work with versican-like molecule to capture space destined to become bone

Their plasma or serum concentrations are used chemically to assess bone metabolism.

RGD, Arg-Gly-Asn; TGF-b, transforming growth factor-b.

Adapted from Lian JB, Stein GS, Canalis E, Robey PG and Boskey AL (1999) Bone formation: osteoblast lineage cells, growth factors, matrix proteins, and

the mineralization process. In: Murray FJ (ed.) Primer on the Metabolic Bone Diseases of Mineral Metabolism, 4th edn, pp. 14–30. Philadelphia, USA:

Lippincott/Williams & Wilkins.

BONE 559

part-achieved by modeling. Bone remodeling involves

resorption and formation of bone and takes place at

the same site (known as the bone-remodeling unit),

leading to no change in bone shape, but allowing

bone rejuvenation, adaptation to stress and strains,

the repair of microfractures and therefore the main-

tenance of mechanical integrity. In addition, bone

remodeling has an important role in the maintenance

of calcium homeostasis. This bone cell-mediated pro-

cess replaces 2–10% of the adult skeleton per annum.

0008 The principal cells that mediate the bone-forming

processes of the mammalian skeleton are the osteo-

blasts that synthesize the bone matrix on bone-

forming surfaces; osteocytes, organized throughout

the mineralized bone matrix, that supports bone

structure; and the protective bone-surface lining

cells. The principal cells that mediate the bone-

resorbing process are the multinucleated giant cells,

known as osteoclasts.

Osteoblasts

0009 Osteoblasts are the cells responsible for the synthesis

and mineralization of type I collagen. They originate

from pluripotent mesenchymal stem cells which, by

following a developmental pathway, they initially

differentiate into preosteosblasts, and then to mature

osteoblasts. A mature osteoblast which is actively

synthesizing bone matrix has many distinctive ultra-

structural characteristics, including a large nucleus,

enlarged Golgi apparatus, and extensive endoplasmic

reticulum. It also has unique biochemical characteris-

tics, including high levels of type I collagen, alkaline

phosphatase, and osteocalcin (Table 1). These cells

form an epithelial-like structure at the surface of

bone where they unidirectionally secrete the osteoid.

In a second step, this matrix than calcifies extracellu-

larly; the role of the osteoblast in this process is still

unclear.

Osteocytes

0010 The osteocytes are the most abundant cells in the

bone matrix, with about 25 000 cells per mm

bone.

However, despite their abundance, their function is

still poorly understood. They originate from mature

osteoblasts which become embedded in the bone

matrix after it becomes mineralized. Osteocytes are

physically different from osteoblasts and have long

protoplasmic extensions which permeate the bone

matrix and allow them to interconnect and communi-

cate with other osteocytes and osteoblasts. Recent

research has shown that osteocytes may act as sensors

for stresses and strains within the bone matrix and

thus may be important in the adaptation of bone to

weight-bearing exercise.

Bone-Lining Cells

0011Bone-lining cells are osteoblasts which are not

actively synthesizing bone and thus are known as

resting osteoblasts or surface osteocytes. They occupy

about 80% of the skeletal surface where they act as a

kind of blood–bone barrier. It is thought that they are

essential for the maintenance of blood calcium levels,

perhaps by actively pumping calcium ions from the

bone fluid compartment to the extracellular fluid

compartment.

Osteoclasts

0012Osteoclasts originate from a lineage different from

that of other bone cells, namely the hemopoietic

system, more specifically from the granulocyte–

macrophage colony-forming unit for granulocytes

and macrophages (CFU-GM). Before developing

into mature resorbing osteoclasts the CFU-GM cells

undergo proliferation and further differentiation,

after which they migrate to the bone surface where

they fuse to become large multinucleated cells. These

large, motile, multinucleated osteoclasts, situated

either on the surface of cortical or trabecular bone,

or within the cortical bone, where they are located at

the tip of the remodeling units, are responsible for the

resorption of bone at these sites.

0013Osteoclast differentiation and activation appear to

be primarily regulated by the osteoblast and its pre-

cursors. Active osteoclasts resorb bone in a closed,

sealed-off microenvironment. This is formed by

attachment of the osteoclast to the mineralized sur-

face by a marginal rim of contractile proteins, called

clear zone or sealing zone. This attachment involves

cell membrane receptors, known as integrins, which

recognize specific peptide sequences in the matrix.

The osteoclast surrounds a chamber lined with

membrane folds (the ruffled border) and secretes

self-generated protons (via a proton adenosine tri-

phosphatase) which then dissolve bone mineral.

Proteolytic enzymes, especially cathepsins (cathepsin

K) and collagenases, are also synthesized by the osteo-

clast and are secreted through the ruffled border into

the extracellular bone-resorbing compartment where

they digest collagen. Recent evidence suggests that

the osteoclast undergoes apoptosis (programmed cell

death) after a cycle of resorption.

Integrated Activity of Bone Cells

(Bone-Remodeling Unit)

0014The bone-remodeling process represents the coordin-

ated actions of osteoclasts and osteoblasts on trab-

ecular bone surface and in Haversian systems. Bone

remodeling occurs in the bone-remodeling units,

560 BONE

which are focal and discrete packets of bone through-

out the skeleton. The remodeling of each packet takes

a finite period (taking up to 6 months but differing in

cortical and cancellous bone, and probably longer

in cancellous bone). The sequence of cellular activity

– the bone-remodeling cycle – within every bone-

remodeling unit is always identical: (1) activation of

osteoclast precursors (possibly by a member of the

tumor necrosis factor (TNF) ligand family, known

as RANK-L (receptor activator for NF-kB ligand)

released by the osteoblast); and then (2) osteoclastic

bone resorption (over a period of 20 days), followed

by: (3) osteoblastic bone formation to repair the

defect (Figure 2). However, the remodeling that

occurs in each packet is geographically and chrono-

logically separated from other packets of remodeling.

It is believed that this can occur because the acti-

vation of the sequence of cellular events respon-

sible for remodeling is locally controlled, possibly

by local mechanisms in the bone microenviron-

ment. In a healthy adult, it has been estimated that

12 new bone-remodeling units are started every

minute in trabecular bone and 3 per minute for

cortical bone.

Coupling of Bone Formation and Bone Resorption

0015 In most circumstances, the coupling of bone forma-

tion to previous bone resorption occurs faithfully.

Packets of bone removed during resorption are

replaced during formation. The cellular and humoral

mechanisms responsible for mediating this coupling

process (or disrupting it, as in some bone diseases)

are still not clear but may involve an osteoblast-

stimulating factor (such as insulin-like growth factor

(IGF)-I, IGF-II, or transforming growth factor-b).

Remodeling Process: Aging and Disease

0016With aging there is a bone-remodeling imbalance,

with the rate of resorption exceeding that of forma-

tion. Bone formation rates have been shown to be

dramatically decreased with age and the percentage

of bone surface with no activity increases and osteo-

blasts disappear. In cortical bone, the ‘physiologic’

imbalance between the two processes leads to an

increased porosity which, in turn, is followed by

mobilization of bone mineral and a decrease in bone

mass. In trabecular bone there are normal or deeper

resorption cavities that are incompletely filled with

new bone by the osteoblasts, leading to a thinning

of the trabeculae, and, in some cases, a perforation of

the trabeculae. This will remove the structural basis

for the following formative period and the final

result will be a hole in the trabecular network, a loss

of bone and bone mineral, and a reduced strength of

the remaining bone. Therefore, an imbalance of the

remodeling process reduces bone mass and causes

detrimental architectural changes and increases

fracture risk.

0017Therefore, the balance between bone formation

and bone resorption, as effected through cellular

Bone-remodeling unit

Resting phase

Collagen formation and mineralization

Formation

Osteoblasts

Bone formation 3−6 months

Osteocytes

Activation

Reversal

Osteoclast apoptosis

Osteoclasts

Bone resorption 10−20 days

fig0002 Figure 2 Bone-remodeling cycle.

BONE 561

events, is an important determinant of bone mass

of an individual at any stage of the life cycle. In

addition, all of the diseases of bone are superimposed

on this normal cellular-remodeling sequence. In dis-

eases such as primary hyperparathyroidism, hyper-

thyroidism, and Paget’s disease, in which osteoclasts

are activated, there is a compensatory and relatively

balanced increase in the formation of new bone. In

elderly patients with osteoporosis, there is a decrease

in mean wall thickness, presumably reflecting

the inability of osteoblasts to repair adequately the

resorptive defects made during normal osteoclastic

resorption.

Regulation of Bone Cell Activity

0018Bone remodeling is regulated by a variety of systemic

hormones and by local regulatory factors (Table 2)

that affect cells of the osteoclast and osteoblast lin-

eage and exert their effects on: (1) the replication of

undifferentiated cell; (2) the recruitment of cells; and

(3) the differentiated function of cells.

tbl0002 Table 2 Systemic hormonal and local regulation of bone remodeling

Typeof regulatory factor/name Effect(s)

Systemic hormones

Parathyroid hormone (PTH) Stimulates differentiation of committed progenitors to form mature

osteoclasts; activates preformed osteoclasts to resorb bone

Parathyroid hormone-related protein (PTHrP) Effects identical to those of PTH on osteoclasts

1,25 (OH)

Potent stimulator of osteoclastic bone resorption

Calcitonin (CT) Potent inhibitor of osteoclastic bone resorption (transient effect); causes

cytoplasmic contraction of the osteoclast cell membrane; causes

dissolution of mature osteoclasts into mononuclear cells; it can also

inhibit osteoclast formation, inhibiting both proliferation of the

progenitors and differentiation of the committed precursors

Insulin Stimulates bone matrix synthesis and cartilage formation; necessary for

normal bone mineralization

Growth hormone (GH) May regulate bone formation

Glucocorticoids May regulate bone resorption

Sex steroids Estrogen deficiency is associated with increased osteoclastic bone

resorption (either via a direct or indirect mechanism)

Thyroid hormones May stimulate osteoclastic bone resorption

Local factors

Interleukin-1 (a, b) Potent stimulators of osteoclasts; stimulates the proliferation of the

progenitors and differentiation of committed precursors into mature

cells; activation of mature multinucleated osteoclasts

Tumor necrosis factor (TNF) Stimulates the proliferation of osteoclast progenitors, causes fusion of

committed precursors to form multinucleated cells, and activates

multinucleated cells to resorb bone.

Colony-stimulating factor 1 Mediates osteoclast formation

Interleukin-18 Inhibitor of osteoclast formation

Osteoclastogenesis-inducing

differentiation factor (ODIF)

Mediator of osteoclastic bone resorption

Interleukin-6 Weak stimulator of osteoclast formation

Interferon-g Inhibitor of osteoclastic bone resorption; inhibits differentiation of

committed precursors to mature cells

Transforming growth factor-b Inhibits osteoclast formation by inhibiting both the proliferation and

differentiation of osteoclast precursors; directly inhibits the activity of

mature osteoclasts; stimulates osteoblast proliferation and synthesis

of differentiated proteins; increased mineralized bone formation

Insulin-like growth factors (I, II) May enhance bone collagen and matrix synthesis and stimulate the

replication of cells of the osteoblast lineage

Fibroblast growth factors (1, 2) Increases bone cell population capable of synthesizing bone collagen

Platelet-derived growth factors Stimulates bone collagen synthesis

Retinoids Stimulatory effect on osteoclasts

Prostaglandins Complex and multiple effects on osteoclasts; prostaglandins of the E

series may stimulate osteoclastic bone resorption; may act as

mediators of pro-bone-resorptive growth factors

Leukotrienes Linked to osteoclastic bone resorption

Adapted from Lian JB, Stein GS, Canalis E, Robey PG, and Boskey AL (1999) Bone formation: osteoblast lineage cells, growth factors, matrix proteins,

and the mineralization process. In: Murray FJ (ed.) Primer on the Metabolic Bone Diseases of Mineral Metabolism, 4th edn, pp. 14–30. Philadelphia, USA:

Lippincott/Williams & Wilkins.

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0019 Systemic regulation of bone turnover is controlled

by numerous hormones, including the mineral homeo-

stasis hormones (parathyroid hormone, calcitonin

and 1,25-dihydroxvitamin D; (See Calcium: Physi-

ology)), estrogen, growth hormone, thyroid hormone,

and others (Table 2). The mineral homeostasis hor-

mones ensure that the skeleton fulfills its metabolic

function as a source of ions, by regulating osteoblast

and osteoclast maturation and activity and thus en-

suring that ions are released or retained by the skel-

eton as necessary. Circulating hormones may act on

skeletal cells either directly or indirectly, modulating

the synthesis, activation, receptor-binding, and bind-

ing proteins of a local growth factor, which in turn

stimulates or inhibits bone formation and bone re-

sorption. It is likely that hormones are important in

the targeting of growth factors to tissue expressing

specific hormonal receptors.

0020 Growth factors may play a critical role in the

coupling of bone formation to bone resorption, and

possibly in the pathophysiology of bone disorders.

The local factors are synthesized by skeletal cells

and include growth factors, cytokines, and prosta-

glandins (Table 2). Growth factors are polypeptides

that regulate the replication and differentiated

function of cells. Growth factors have effects on

cells of the same class (autocrine factors) or on cells

of another class within the tissue (paracrine factors).

Bone Development and Growth

0021 Bone is often described as developing by two different

methods: intramembranous (in membrane) and endo-

chrondral (in cartilage) ossification. The fundamental

process is, however, similar. The osteoid is laid down

by osteoblasts, and this then becomes calcified. The

flat bones (such as the bones of the calvarium of the

skull) are formed by intramembranous ossification,

whereas the basal bones of the skull and the majority

of bones of the skeleton, including the long bones, are

formed by endochrondral ossification. The main

difference between the processes is the presence of a

cartilaginous phase in the latter.

Endochondral Ossification (Development of Long

Bones)

0022 Formation of a cartilage model Long bones begin as

cartilaginous regions in the early embryo. Mesenchy-

mal cells proliferate and differentiate into prochon-

droblasts and then into chrondroblasts. These cells

secrete the cartilaginous matrix. Like the osteoblasts,

the chrondoblasts become progressively embedded

within their own matrix, where they lie within the

lacunae; they are then called chrondocytes. Unlike the

osteocytes, they 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

perichrondium), the mesenchymal cells continue to

proliferate and differentiate. They lay down a layer

of osteoid, which immediately calcifies, so becoming

a collar of periosteal bone directly in contact with

the cartilaginous model. This is called appositional

growth. Later on, the chrondocytes enlarge progres-

sively, become hypertrophic, and undergo apoptosis.

0023Longitudinal growth, growth in diameter, and shape

modification The embryonic cartilage is avascular.

During its early development, a ring of woven bone is

formed by intramembranous ossification in the future

midshaft area under the perichondrium (which is then

the periosteum). Just after the calcification of this

woven bone, blood vessels (preceded by osteoclasts)

penetrate the cartilage, bringing the blood supply that

will form the hematopoietic bone marrow.

0024The growth plate in a growing long bone has a

proliferative zone at the top, where chondroblasts

divide actively, while their more mature descendants

synthesize the matrix and enlarge, thereby producing

longitudinal growth. Ultimately, the chondrocytes

hypertrophy and calcify their matrix. Osteoclasts pre-

sent in the marrow cavity invade this calcified cartil-

age, destroying the horizontal septa separating the

chondrocytes. After osteoclastic resorption, osteo-

blasts differentiate and form a layer of woven bone

on top of the cartilaginous remnants of the septa. This

is the first remodeling sequence, and cartilage is re-

placed by woven bone. Still lower in the growth plate,

this woven bone is subjected to further remodeling, in

which the woven bone and the cartilaginous rem-

nants are replaced with lamellar bone, representative

of mature trabecular bone. Complete calcification of

the growth plate at the end of puberty marks the end

of longitudinal growth.

0025Growth in diameter of the shaft is the result of a

deposition of new intramembranous bone beneath

the periosteum that will continue throughout life.

The midshaft is narrower than the metaphysis,

and the growth of a long bone progressively destroys

the lower part of the metaphysis and transforms it

into a diaphysis, accomplished by continuous resorp-

tion by osteoclasts beneath the periosteum.

Intramembranous Ossification (Development of

Flat Bones)

0026In intramembranous ossification, a group of

mesenchymal cells within a highly vascularized area

of the embryonic connective tissue proliferates and

differentiates directly into preosteoblasts and then

into osteoblasts. These cells synthesize and secrete

osteoid which is calcified to become woven bone.

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Blood vessels incorporated between the woven bone

trabeculae will form the future hematopoietic bone

marrow. Later, the woven bone is remodeled and is

progressively replaced by mature lamellar bone. In

early human fetal life, resorption and apposition

begin to take place so that the cancellous bone occu-

pies the center of the mass while a layer of cortical

bone is formed on each surface by the continuous

addition of new sheets of bone by active osteoblasts.

Osteoclasts resorb bone from the inner surface to

maintain proportional thickness and shape.

Age-Related Changes in Bone Mass

0027 Bone mass in later life depends on the peak bone mass

achieved during growth and the rate of subsequent

age-related bone loss. Therefore, development of

maximal bone mass during growth and reduction

of loss of bone later in life are the two main strategies

of preventing osteoporosis. Several factors are

thought to influence bone mass. These can be broadly

grouped into factors that cannot be modified, such as

gender, age, body (frame) size, genetics, and ethnicity,

and those factors that can be modified, such as

hormonal status (especially sex and calciotropic hor-

mone status), lifestyle factors, including physical

activity levels, smoking and alcohol consumption pat-

terns, and diet. The interaction of these genetic,

hormonal, environmental, and nutritional factors in-

fluences both the development of bone to peak bone

mass at maturity and its subsequent loss.

0028 After the initial formation and development of

bone, and during childhood and adolescence, there

is a rapid linear and appositional skeletal growth, the

former reaching a maximum between ages 15 and 20

years. Bone mass then continues to increase by appos-

itional growth and the peak bone mass is probably

attained during the third decade of life (Figure 3),

although the exact timing is not certain and may

vary between different regions of the skeleton. Peak

bone mass and the subsequent rate of loss of bone are

important determinants of risk of osteoporosis in

later life. The regulation of peak bone mass is not

fully understood but a number of factors have been

identified. Of these, the most important are genetic

influences; other determinants, which are potentially

modifiable, include physical activity, nutritional

factors, and hormonal status:

0029 Genetic factors – studies in twins show that 60–

80% of peak bone mass is genetically determined;

there is also some evidence that some aspects of

bone architecture and geometry relevant to bone

strength are inherited. The heritability of peak bone

mass is believed to be polygenic (i.e., influenced by

numerous genes) and there is currently a lot of

interest in identifying these genes.

0030Nutritional factors adequate intakes and status of a

number of dietary components and nutrients are

thought to be important in achieving optimal

peak bone mass. These include calcium, phos-

phorus, magnesium, while high salt intakes may

be detrimental.

0031Physical activity – physical activity has important

effects on bone growth and architecture during

childhood and adolescence.

0032Hormonal status – primary hypogonadism in either

sex is associated with low bone mass, while sec-

ondary amenorrhea in women (due to anorexia

nervosa, excessive exercise, or disease) results in

low peak bone mass.

Age-Related Bone Loss

0033After peak bone mass has been attained, there is a

period of consolidation in which the transverse

diameter of the long bones and vertebrae continues

to increase by subperiosteal appositional growth. The

age at which bone loss commences is uncertain but is

believed to be around the age of 40 years in both men

and women. Bone loss then continues throughout life,

affecting both cortical and cancellous bone through-

out the skeleton. In men, bone loss averages between

0.5 and 1.0% per annum. In women, there is an

acceleration in the rate of bone loss around the time

of the menopause to about 2%, although rates of

bone loss vary widely, from less than 1% to 6% per

annum. In the early postmenopausal years, bone loss

from the spine exceeds that at other sites and overall

it is estimated that, in women, approximately 35%

and 50% of cortical and cancellous bone respectively

are lost from the skeleton over the course of a life-

time.

020

Age (years)

Bone mass

Peak bone mass

Age-related bone loss

Men

Menopausal

bone loss

Women

40 60 80

fig0003Figure 3 Age-related changes in bone mass in men and

women.

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