MEDICINE

This text is a translation from the original German which should be used for referencing. The German version is authoritative.

REVIEW ARTICLE

Muscle and Bone: a Functional Unit Eckhard Schönau, Oliver Fricke

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

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

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DIAGRAM 1

The regulation of the development of bone strength

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 development In 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 regulatory circuit 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. Dtsch Arztebl 2006; 103(50): A 3414–9 ⏐ www.aerzteblatt.de

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DIAGRAM 2

The relevance of bone geometry to the development of bone strength

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 in bone 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 adolescence There 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 bones hollow? 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 Dtsch Arztebl 2006; 103(50): A 3414–9 ⏐ www.aerzteblatt.de

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DIAGRAM 3

Bone analysis (radius) with peripheral quantitative computerized tomography

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

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DIAGRAM 4

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

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New diagnostic concept: bone and muscle as a functional unit The "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 DIAGRAM 5

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

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 osteogenesis imperfecta, 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 future Scientific 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 consideration of body size leads to errors of interpretation and to false estimates of bony stability and the risk of fracture. Dtsch Arztebl 2006; 103(50): A 3414–9 ⏐ www.aerzteblatt.de

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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. A disturbance 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 Statement Prof. Schönau has received financial support from Novotec Medical GmbH. Dr. Fricke declares that he has no conflict of interest according 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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15. Rauch F, Neu CM, Wassmer G, Beck B, Rieger-Wettengl G, Rietschel E, Manz F, Schoenau E: Muscle analysis by measurement of maximal isometric grip force: new reference data and clinical applications in pediatrics. Pediatr Res 2002; 51: 505–10. 16. Remer T, Boye KR, Hartmann M, Neu CM, Schoenau E, Manz F, Wudy SA: Adrenarche and bone modeling and remodeling at the proximal radius: weak androgens make stronger cortical bone in healthy children. J Bone Miner Res 2003; 18: 1539–46. 17. Schoenau E, Neu CM, Mokov E, Wassmer G, Manz F: Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls. J Clin Endocrinol Metab 2000; 85: 1095–8. 18. Schoenau E, Werhahn E, Schiedermaier U, Mokow E, Schiessl H, Scheidhauer K, Michalk D: Influence of muscle strength on bone strength during childhood and adolescence. Horm Res 1996; 45 (Suppl. 1): 63–6. 19. Schoenau E, Neu CM, Beck B, Manz F, Rauch F: Bone mineral content per muscle cross-sectional area as an index of the functional muscle-bone unit. J Bone Miner Res 2002;17: 1095–101. 20. Bechtold S, Ripperger P, Bonfig W, Pozza RD, Haefner R, Schwarz HP: Growth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography. J Clin Endocrinol Metab 2005; 90: 3168–73. 21. Klaus G, Paschen C, Wuster C, Kovacs GT, Barden J, Mehls O, Scharer: Weight-/height-related bone mineral density is not reduced after renal transplantation. Pediatr Nephrol 1998; 12: 343–8. 22. Roth J, Palm C, Scheunemann I, Ranke MB, Schweizer R, Dannecker GE: Musculoskeletal abnormalities of the forearm in patients with juvenile idiopathic arthritis relate mainly to bone geometry. Arthritis Rheum 2004; 50: 1277–85. 23. Schweizer R, Martin DD, Schwarze CP, Binder G, Georgiadou A, Ihle J, Ranke MB: Cortical bone density is normal in prepubertal children with growth hormone (GH) deficiency, but initially decreases during GH replacement due to early bone remodeling. J Clin Endocrinol Metab 2003; 88: 5266–72. 24. Karlsson MK, Linden C, Karlsson C, Johnell O, Obrant K, Seeman E: Exercise during growth and bone mineral density and fractures in old age. Lancet 2000; 355: 469–70. 25. Pajamaki I, Kannus P, Vuohelainen T, Sievanen H, Tuukkanen J, Jarvinen M, Jarvinen TL: The bone gain induced by exercise in puberty is not preserved through a virtually life-long deconditioning: a randomized controlled experimental study in male rats. J Bone Miner Res 2003;18: 544–52.

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This text is a translation from the original German which should be used for referencing. The German version is authoritative.

e16. Schoenau E: The "functional muscle-bone unit": a two-step diagnostic algorithm in pediatric bone disease. Pediatr Nephrol 2005; 20: 356–9. e17. Fricke O, Weidler J, Tutlewski B, Schoenau E: Mechanography – a new device for the assessment of muscle function in pediatrics. Pediatr Res 2006; 59: 46–9. e18. Bechtold S, Ripperger P, Dalla Pozza R, Schmidt H, Hafner R, Schwarz HP: Musculoskeletal and functional muscle-bone analysis in children with rheumatic disease using peripheral quantitative computed tomography. Osteoporos Int 2005; 16: 757–63. e19. Sanchez CP, Salusky IB, Kuizon BD, Ramirez JA, Gales B, Ettenger RB, Goodman WG: Bone disease in children and adolescents undergoing successful renal transplantation. Kidney Int 1998; 53: 1358–64. e20. Third International Congress on Bone Health in Childhood in Sorrent. Bone 2005; 26 (Suppl.). e21. Winzenberg T, Shaw K, Fryer J, Jones G: Effects of calcium supplementations on bone density in healthy children: meta-analysis of randomised controlled trials. BMJ 2006; 333: 775. Corresponding author Prof. Dr. med. Eckhard Schönau Klinik und Poliklinik for Kinderheilkunde Klinikum der Universität zu Köln Kerpener Str. 62 D-50924 Köln (Cologne), Germany

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