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T he close relation between bone mass and the risk of fracture provides the basis for the

recommendations of the World Health Organization (WHO) regarding the diagnosis

and characterization of osteopenia and osteoporosis (1). The assessment and therapeutic

alteration of bone mass are thus considered to be key elements in the management of osteopenia.

"Peak bone mass" is optimized in order to lower the risk of fracture in old age.

The prevention,diagnostic evaluation, and treatment of osteoporosisThe acquisition of a large amount of bone mass in childhood and adolescence has been

thought to protect the individual against fractures at later stages of life. This article deals

with research findings on skeletal development that have been published in the last

10 years. We will critically discuss whether the current conception of bone health as being

largely a matter of bone mass really does justice to the biological principles of skeletal

development in childhood and adolescence.

The central question is whether "optimal bone-building" in childhood and adolescence

is truly an effective way to prevent fractures and/or osteoporosis in adulthood (2, 3, 4, e1,

e2, e3, e4). Confirmation of this hypothesis would require controlled studies with data

collected over a 60- to 80-year time span, and, obviously, no such studies have been

published to date. In fact, the usefulness of an isolated analysis of bone mass in childhood,adolescence, or even adulthood is a matter of current debate, and the concept underlying it

is increasingly held to be an oversimplification. Multiple authors also question whether

there has been adequate research into the relationship between the development of bone

strength in childhood and adolescence and the maintenance of bone strength in adulthood

(5, 6, e5, e6). In children, for instance, the bone mass parameters have been shown to depend

on height, among other factors. Children of short stature have smaller bones and less bone

mass, while tall children have more bone mass, though their ratio of height to bone mass is

roughly equal. The relevant question for the assessment of "bone health" is, therefore,

whether the individual's bone mass is appropriate for his or her height (and therefore for the

proper functioning of the skeletal system). This simple principle was neglected until

recently; across the world, many children of short stature or in the low normal range for

height were wrongly diagnosed as suffering from osteopenia or osteoporosis. Similar

considerations apply to shorter adults. A further source of unnecessary confusion in the

Dtsch Arztebl 2006; 103(50): A 3414–9 ⏐ www.aerzteblatt.de 1

M E D I C I N E

SUMMARY Introduction: This review deals with the relationship of muscle force and mass to bone mass

and geometry in the developing skeleton of children and adolescents. Methods: Results from

studies in the last ten years are discussed with reference to Harold Frost's "mechanostat

hypothesis." Results: Bone mass and geometry follow the development of body mass and muscle

strength in children and adolescents. Therefore, bone is adapted to applied biomechanical

forces. Measuring the ratio of muscle force to bone strength is an approach to distinguish

between a primary and a secondary bone disease. Primary bone diseases are characterized by

dysfunctional adaptation of bone to biomechanical forces. Secondary bone diseases, in contrast,

are characterized by normal adaptation of bone to loaded forces, but a decline of muscle force

(sarcopenia). Discussion: These observations induced us to introduce the "functional muscle-bone

unit" into the diagnosis of pediatric bone diseases. The ratio of two parameters – bone strength

on the one and biomechanical forces on the other side – is a reasonable diagnostic tool to

distinguish between primary and secondary bone diseases.

Dtsch Arztebl 2006; 103(50):A 3414–9.

Keywords: osteoporosis, muscle-bone unit, osteodensitometric measurement

Klinik und Poliklinik für Kinderheilkunde,Universtität zu Köln (Prof. Dr.med. Schönau,Dr.med. Fricke)

This text is a

translation from

the original

German which

should be usedfor referencing.

The German

version is

authoritative.

REVIEW ARTICLE

Muscle and Bone: a Functional Unit

Eckhard Schönau, Oliver Fricke



evaluation of bone tests in children is the tendency to equate, incorrectly, the physical

concepts of bone density and bone mass. Bone density is bone mass divided by bone

volume, and is accordingly measured in milligrams per cubic centimeter (mg/cm3). Bone

mass is the absolute amount of bone that is present, measured in milligrams (mg) (7).

Consequently, for the proper interpretation of bone analyses in children, one should bear

in mind that low bone density implies either an altered material property of bone, e.g., a less

than normal amount of mineral per volume of bone (as in rickets or osteomalacia), or else

an altered tissue structure of bone, e.g., excessively thin trabeculae or too few trabeculae

per volume of spongiosa. Yet low bone mass in children of short stature – particularly children

suffering from chronic diseases – is a normal finding. Stated another way, low bone mass

may be due to low bone density (a pathological finding) or to small bone size (a physiological

adaptation). This seemingly trivial fact should always be remembered in quantitative

analyses of the skeletal system (8).

An overview of a representative sample of studies reveals that, over the last 10 years,

increasing importance has been attached to the assessment of bone geometry in childhood

and adolescence, and of the bone strength that results from it, in addition to the measurement

of bone mass and density. A major advance has taken place in the biological conception of

skeletal development. It is now finally understood that the shape and size of a part of the

skeleton are a function of the biomechanical demands placed on it.

The mechanostat: a regulator of skeletal developmentIn 1892, the German anatomist Julius Wolff described the "law of transformation of bone"

(9), according to which the skeletal system adapts itself to external conditions (forces). In

the 1960's this "law" was further elaborated through the observations of the American

orthopedist Harold Frost. The resulting "mechanostat hypothesis" postulated a regulatorycircuit for bone development, as depicted in diagram 1 (10, e7, e8).

At the center of the regulatory circuit, there is a "mechanostat," which analyzes the bone

deformations produced by active muscular contraction and uses the result to modulate bone

strength by regulating the activity of bone cells (osteoblasts and osteoclasts). Strong forces

during muscle development (physical activity) promote the buildup of bone; weak forces

(immobility) lead to bone loss and a reduction of bone strength. Stated another way, bone

strength is always adapted to the mechanical forces acting on bone.

In recent decades, many scientists and physicians rejected this theory as being "too

mechanical." Current research, however, has identified the osteocyte network as the

"biological correlate" of the mechanostat and has thus led to renewed interest in the

interaction of mechanics and biology in bone development, not only among physicians, but

among basic researchers as well (11).

Within the regulatory circuit (diagram 1), mechanical factors, such as the maximal force of the musculature, are strictly separated from non-mechanical ones, such as hormones, nutrients,

and medications, which have modulating effects.


M E D I C I N E

The regulation of the development of bone strength

DIAGRAM 1



Examples include the known effects of

> of parathormone on osteoblast activity,

> of biphosphonates on osteoclast activity,

> of estrogen (possibly) on osteocyte sensitivity,

> of calcium and phosphate on spontaneous mineralization, and

> of growth hormone and testosterone on muscle development.

Non-mechanical factors cannot substitute for mechanical factors in the regulatory circuit.

The current view is that one cannot separate "important" from "unimportant" factors inbone development; rather, all of the relevant factors must act synergistically. Though it

would be comforting to believe that "calcium makes the bones strong," because giving

calcium supplements is easy, the current data suggest that a new point of view must be

adopted, leading to different recommendations than before (e21).

Calcium deficiency in childhood is the cause of rickets, a condition in which the bone

substance is inadequately mineralized. Osteoporosis, on the other hand, is a deficiency of

bone substance itself, due either to inadequate bone formation or to accelerated bone loss.

Osteoporosis is not due to inadequate bone mineralization.

Important properties of bone in childhood and adolescenceThere are good reasons to believe that evolution favors the principle of minimum expense

(in energy and material) for maximal success (adequate bone strength for physical activity).

If the goal were to have the heaviest bones possible, then why are mammalian boneshollow? Would it make any sense to transport heavy bones? On the other hand, if the goal

were to have the densest bones possible, then why do persons with abnormally dense bones


M E D I C I N E

DIAGRAM 2The relevance of bone geometry

to the development of bone

strength



– e.g., persons suffering from osteogenesis imperfecta – sustain so many fractures?

Diagram 2 depicts the interrelationship of density, mass, and bone strength (7, 12, e9).

Bone strength is a function of the material properties of bone (density), of the quantity of

bone that is present (mass), and of the distribution of bone around its center of mass

(geometry). Minor changes in bone geometry, e.g., an increase in bone diameter, can result

in major increases in bone strength.

Skeletal development: a function of the muscular forces acting on boneIn the Dortmund Nutritional and Anthropometric Longitudinally Designed Study (the

DONALD study), the relationship between muscle and bone development postulated in the

mechanostat hypothesis was studied over time in 349 normal children and adolescents aged

6 to 19 years (183 girls, 166 boys) and in their mothers aged 29 to 59 (201 mothers). The

DONALD study is a longitudinal study of the effect of nutrition and other "lifestyle" factors

on children's development (e10).

Musculoskeletal development was assessed with peripheral quantitative computerized

tomography (pQCT) of the non-dominant forearm. The site of measurement was described

in terms of the ratio of the distance of the CT cross-sectional image from the distal ulnar

epiphysis to the overall length of the bone. Diagram 3 depicts the location of the CT

sections along the radius and illustrative findings for bone density (spongiosa density,

cortical density), bone mass (bone mineral content = BMC), and bone strength (bone

strength index = BSI).It has been shown in many experimental studies of animal bones, and in fragility

studies of human bones obtained at autopsy, that the parameter BSI is a highly reliable

predictor of the force necessary to break a bone. The upper and lower panels of diagram 4

depict the bone parameters BMC and BSI, respectively, as a function of the cross-

sectional area of muscle in the forearm. An age-independent linear relationship is

evident (children and their parents appear on the same line). These data support the

relationship between the forces on bone and bone development postulated by Wolff in

1892, as well as Frost's mechanostat hypothesis of 1964. In contrast, the development of

spongiosa density in the distal portion of the radius was found to be largely independent

of both age and muscle force in normal, healthy individuals. In the authors' clinical

experience, this property of spongiosa density makes it a useful screening parameter for

the detection of early bone loss due to congenital disorders or chronic diseases. More

detailed information on the DONALD study, the interrelationship of muscle and bone,methods of analysis, and reference values can be found in a number of publications

(12–17, e11–e15).


M E D I C I N E

Bone analysis (radius) with peripheral quantitative computerized tomography

DIAGRAM 3




M E D I C I N E

Development of (a) bone mass and (b) bone strength as a function of muscle development

DIAGRAM 4



New diagnostic concept: bone and muscle as a functional unitThe "functional muscle-bone unit" was first described in 1996 on the basis of pilot studies

on the development of muscle and bone in childhood and adolescence (18). Because

muscle and bone are closely functionally linked, it was recommended that the diagnostic

evaluation of skeletal diseases should always include an assessment of the musculature. If

the development and maintenance of the skeletal system depend on the proper functioning

of the muscles, then the muscles should certainly be examined as well. This concept

represents a paradigm shift. Until very recently, bone parameters in childhood, adolescence,

and adulthood were compared to normal values for chronological age, i.e., averaged values

for a population of like age. The concept of the "functional muscle-bone unit," in contrast,

requires consideration of bone parameters not in relation to age, but in relation to muscle

parameters. In order to put this concept into practice, we recommend that the muscle-bone

unit be evaluated in two steps (diagram 5) (19, e16).

In the first step, muscle development is evaluated. Body length (height) is taken as an

individual reference value. The development of height is very closely correlated with that

of muscle mass (19, e17), as can easily be understood from a teleological point of view.

Larger bones are heavier, and moving them requires larger forces and torques, which, in

turn, have to be generated by bigger and stronger muscles.

In the second step of the recommended algorithm, skeletal adaptation is assessed, so that

skeletal diseases can be divided into primary and secondary types. In primary skeletal

diseases, the skeleton is poorly adapted to muscular forces; examples include osteogenesisimperfecta, juvenile idiopathic osteoporosis, and iatrogenic bone disorders (side effects of

medication). In secondary skeletal diseases, the muscles do not adequately stimulate bone

development because of, e.g., primary muscular diseases, the catabolic state in chronic

illness, or physical inactivity.

The two-step algorithm enables a separation of cause and effect. "Osteoporosis" is

considered to be a manifestation of disease, rather than a disease in its own right, and

greater attention is paid to pathophysiology.

Summary and prospects for the futureScientific study of the interaction of muscular and skeletal development in childhood and

adolescence has revealed that the skeletal system continually adapts itself to the external

forces placed on it, i.e., to the maximal muscular forces generated during everyday physical

activity. The use of age-indexed reference values for bone mass without any considerationof body size leads to errors of interpretation and to false estimates of bony stability and the

risk of fracture.


M E D I C I N E

Diagnostic algorithm in patients with fractures and/or osteopenia/osteoporosis

DIAGRAM 5



The manufacturers of various types of equipment for quantitative bone analysis have

already taken some first steps to change their software for children and adolescents. Bone

mass is now considered in relation to body size (height), and therefore indirectly in relation

to bone size. Nonetheless, the functionality of the bone-muscle unit as a whole continues to

be neglected.

The characterization of muscle mass and muscle function permits a more precise

diagnostic evaluation of "osteoporosis," which is not a disease in itself, but rather a manifestation

of disease. Adisturbance of muscle development, leading to a secondary disturbance of the

skeletal system, has been found to be present in many chronic diseases, such as juvenile

rheumatoid arthritis, renal failure, status post renal transplantation, mucoviscidosis, growth

hormone deficiency, and others (20, 21, 22, 23, e18, e19). These results have led to a

fundamental change of perspective in pediatrics. Current studies focus on the intensification

of muscle formation and maintenance in chronic disease. This viewpoint is of major

importance in current discussions of the best way to prevent osteoporosis.

The interrelationships discussed in this paper, as well as current research findings that

were presented recently in Sorrento at the Third International Congress on Bone Health in

Childhood, imply that much more attention needs to be paid to the optimal development of

muscle mass and muscle function than was the case in the past (e20). It is particularly

important to realize that "peak bone mass" in adolescence does not provide any lasting

protection against osteoporosis in advanced age. Muscle and bone are a functional unit that

constantly adapts to changing conditions (24, 25). Our improved understanding of the

function of the muscle-bone system is making it increasingly clear that physical activity in

childhood and adolescence, which should be continued into adulthood, is an important

precondition for the long-term preservation of optimal physical mobility.

Conflict of Interest StatementProf. Schönau has received financial support from Novotec Medical GmbH. Dr. Fricke declares that he has no conflict of interestaccording to the Guidelines of the International Committee of Medical Journal Editors.

In 2003, the Hufeland Prize for 2002 was awarded for a portion of the work described in this article.

Manuscript received on 27 July 2005, final version accepted on 19 June 2006.

Translated from the original German by Ethan Taub, M.D.

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Corresponding authorProf. Dr. med.Eckhard SchönauKlinik und Poliklinik for KinderheilkundeKlinikum der Universität zu KölnKerpener Str. 62D-50924 Köln (Cologne), Germany


M E D I C I N E

This text is a

translation from

the original

German which

should be used

for referencing.

The German

version is

authoritative.

Documents

muscle bone unit